1. INTRODUCTION:

Breast cancer (BC) is the most commonly diagnosed cancer among US women excluding nonmelanoma of the skin. It is the second most common cause of death from cancer among all women following lung cancer but the leading cause of cancer death among Black and Hispanic women. An estimated 30% instances of breast cancer are attributed to modifiable risk factors such as excess body weight, physical inactivity and alcohol intake and thus may be preventable^{1, 20}.

Disturbance in sleep has been identified as a common clinical issue for cancer patients and it is frequently the focus of pharmacological treatments. Prevalence estimates of sleep disturbance vary widely ranging from as low as 24% to as much as 95%².

Breast cancer is the most prevalent malignancy in women, with more than 316,000 instances reported to the US each year. The majority of breast cancers start as invasive ductal carcinoma (IDC) or ductal carcinoma-in situ (DCIS) within the breast milk ducts. The accumulation of mutational alterations most often in the ductal epithelium leads to the progression of breast cancer. Many components within the ductal microenvironment including soluble components like growth factors, cytokines, chemokines and prostaglandins as well as cellular components like immune cells, adipocytes, fibroblasts and the microbiome can have an impact on the onset and course of these alterations³.

Based on both molecular and histological evidence, BC could be categorized into three groups; BC expressing hormone receptor (estrogen receptor (ER+) or progesterone receptor (PR+)), BC expressing human epidermal receptor 2 (HER2+) and breast cancer that is triple-negative (TNBC) (ER−, PR−, HER2−). Furthermore, the TNBC divided into six categories; basal-like 1 (BL-1), basal-like 2 (BL-2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem cell-like (MSL), and luminal androgen receptor (LAR)^4,14,15.

Cancer survivors have reported more frequent and severe exhaustion in comparison to others who have never had cancer. In the case of cancer, exhaustion may result from the disease's symptoms, the course of therapy, or psychological reactions to the illness. Fatigue is a highly upsetting symptom that typically does not go away with sleep in cancer patients. Cancer-related fatigue, or CRF, is a multifaceted notion affecting the physical, cognitive, and affective domains (less motivation, impaired concentration and attention, and less energy)⁷.

In spite of the fact that the disease is global, there are significant regional differences in its incidence, mortality, and survival rates. These variations may be caused by a variety of variables, including environment, genetics, lifestyle, and population structure. The prevalence of breast cancer has increased due to changes in risk factors, and this number is rising daily⁹.

Anti-estrogen is very effective in lowering the incidence of breast cancer; nevertheless, prolonged use may result in a number of negative consequences. Aromatase inhibitors also are efficient in treating female patients with early-stage breast cancer.

Nonetheless, a few studies raise the possibility of cardiotoxicity with aromatase inhibitors. Anti-angiogenesis medications can stop breast cancer from growing and developing, which can cause ischemia death. Growing research revealed that monoclonal antibody medications could increase patients' chances of survival and had a strong anticancer impact. These drugs, however, were limited to use in individuals with HER2-positive breast cancer, and the majority of them had significant adverse effects that could worsen following treatment. When treating breast cancer, anthracyclines are superior to several other chemotherapy medications. However, it also has adverse effects, like nail discoloration and heart damage.

Clinical data found that numerous natural compounds derived from plants have been shown to have a strong anti-breast cancer effect like Paclitaxel, vincristine, cantharidin sodium injection, and Magnolol. These organic substances have demonstrated exceptional medicinal benefits when used in chemotherapy for the treatment of cancer¹¹.

Mammographic density and prior benign breast cancer are two greater importance of risk factors for breast cancer. Still, it is unclear which component plays the biggest part in the pathophysiology of breast cancer. Therefore, Cancer of the breast is now the second most typical reason for mortality among women. The chemotherapeutic chemicals that are employed in its therapy are primarily derived from plants, specifically lichens, fungus, fruits, leaves, and flowers. In botany, "herb" refers to plants that have nonwoody stems and produce fruits and seeds. The preservation of human health has benefited greatly from the use of these plants and herbs. Because herbal remedies contain naturally occurring active components that can support human health, the public is becoming more interested in them than in synthetic medications²⁰.

The study of breast cancer is crucial because it will help us reduce the enormous human and financial costs associated with the disease as we gain a better understanding of these conditions. We now know more about breast cancer than we did a few years ago, from investigating ways to avoid the disease to understanding why certain families are more susceptible. Every day, research improves care, yields better results and changes people's lives. It is a subject of concern as this implies the need for instructional and awareness programs targeting younger members of the society, to establish early practices of breast exams. The purpose of this study was to evaluate people's awareness and knowledge regarding breast cancer.

1.1 A recent study on Breast Cancer:

Based on statistics gathered by AIIMS from hospitals throughout the city, the most common types of cancer diagnosed in Delhi are breast cancer in women. Physicians have also noted that women under 40 years of age accounted for 30% of all incidences of breast cancer⁸.

Based on available data, out of one lakh individuals, approximately 35 women were expected to have breast cancer in 2015. In a span of seven years, the number of patients with breast cancer increased from 2,657 to 3,611, a 35.9% increase. Data on cancer patients is gathered by the Institute Rotary Cancer Hospital (IRCH), AIIMS, population-based cancer registry, from a variety of sources, including the Department of Vital Statistics of the New Delhi Municipal Committee and Delhi Municipal Corporation, as well as 182 government and private hospitals and 250 assisted living facilities^1,7,16.

According to Professor MD Ray of AIIMS's surgical oncology department, women under the age of forty account for 30% of all breast cancer infections, and this percentage is steadily rising. “Lifestyle factors such as smoking, drinking a high-fat diet, late nights, late rising and a sedentary life are mainly responsible for this type of cancer. The growing tendency to opt for calorie-rich fast food, instead of fresh fruits and vegetables, is also a cause of concern. An imbalanced lifestyle can cause cancer for sure”. Even every resident in a metropolis may be at risk due to pollution. The negative consequences of smoking are felt by non-smokers as well because of contaminated air.

People can be at risk from excessive exposure to chemicals including pesticides, fertilizers, and toilet cleansers. According to data from the health ministry, 14,057 deaths in Delhi attributable to cancer were recorded in 2020; in 2021 and 2022, 14,494 and 14,917 deaths, respectively, were reported^1,7.

Figure 1: Rising incidence of breast cancer among women compared to other cancers between 2015 and 2022

1.2 Genetic risk factor:

Collectively, parent-inherited gene alterations are thought to be responsible for 5–10% of breast cancer cases. An inherited mutation in either the BRCA1 or BRCA2 gene is the most typical reason for hereditary breast cancer. Women who carry a BRCA1 mutation have a lifetime risk of 55–65% for breast cancer, according to statistics. A BRCA2 mutation carries a 45% lifetime risk for women. A woman with a BRCA1 or BRCA2 gene mutation has, on average, a 70% probability of developing breast cancer by the time she is 80 years old. The effects of the mutation are correlated with the number of other relatives who additionally have breast cancer, since the likelihood of developing breast cancer increases in conjunction with the number of affected family^4,9,22.

It is estimated that between 5 and 10% of cases of breast cancer are hereditary, which means that the abnormalities in the genes that cause the disease are inherited straight from one's parents.

BRCA1 and BRCA2: An inherited mutation in either of the two genes is the most frequent cause of hereditary breast cancer. These genes aid in the production of proteins in healthy cells that fix broken DNA. These genes' mutated forms may cause aberrant cell proliferation, which may result in cancer.^4,9

· It is more likely to get breast cancer if you received a parent's mutant copy of either gene.

· A woman who carries a BRCA1 or BRCA2 gene mutation has a 7 in 10 probability, on average, of developing breast cancer by the time she is 80 years old. The number of other family members who have had breast cancer influences this risk as well. (It increases if additional family members are impacted.)

· Women who carry one of these mutations are more likely to get cancer in both breasts and to receive a breast cancer diagnosis earlier in life.

· Women who carry one of these gene mutations are also more likely to develop certain other malignancies, including ovarian cancer. (Men who inherit one of these mutations in the genes are also more likely to develop breast and other cancers.)

· While they can affect anyone, BRCA mutations are more common in Ashkenazi (Eastern European) Jews in the United States than in other racial and ethnic groupings.

Environmental factors:

Ionizing radiation exposure is the only known environmental factor that raises the risk of breast cancer. Two potential risk factors for breast cancer are exposure to hazardous chemicals and contaminants in the environment. Exposure to environmental pollutants may increase the risk of breast cancer, but the exact quantity and type of exposure, the age at which exposure occurs, and the characteristics of the pollutant will probably all play a role. Air pollution: Postmenopausal breast cancer was more common in women who lived in areas with higher air pollution levels of lead, mercury, and cadmium.

Common chemical exposures can alter when a child reaches puberty. For instance, early breast development was observed in girls exposed to high concentrations of triclosan, an ingredient in various antimicrobial soaps. Additionally, girls exposed to high levels of benzophenone-3, found in some sunscreens, had later breast development.

The chance of developing breast cancer increases with exposure to endocrine disrupting chemicals during these periods: her prenatal development, puberty, pregnancy and menopausal transition.

It was discovered through testing that almost 300 chemicals used in food processing, personal care products, flame retardants, insecticides, and other applications affected hormones known to raise the risk of breast cancer. Tested substances might be present in water and air pollution.

1.3 Non-genetic risk factor:

1.3.1 Family history of breast cancer: Cases within breast cancer that have happened are referred to as having a history of the illness in the family among close blood relatives, such as parents, siblings, and children. It is an important consideration in assessing an individual’s chance of getting breast cancer since the disease's development can be significantly influenced by genetics^4,43,44.

Certain genetic mutations, such as mutation in the BRCA1 and BRCA2 genes, are linked to a higher likelihood of arising breast cancer. If these changes can be discovered in a family, it can significantly raise the likelihood of developing breast cancer among family members²².

1.3.2 Race and ethnicity: Race and ethnicity can be very important in the incidence, treatment, and outcomes for cancer within the breast. It's crucial to remember that differences in the prognosis of breast cancer between various racial and ethnic groups are multifactorial and result from a complex interplay of social, economic, genetic, and healthcare system factors^4,46.

1.3.3 Certain benign breast Carcinoma: Benign breast conditions are non-cancerous changes or abnormalities in breast tissue. While they are not cancerous, they can cause discomfort, pain, or other symptoms^4,47,48.

1.3.4 Certain proliferative breast lesions: Proliferative breast lesions refer to changes in breast tissue where cells are actively growing and dividing more than normal but have not yet become cancerous. Frequently, these lesions are classified as non-atypical or atypical according to the extent of cell abnormality^4,49,50.

1.3.5 Lobular carcinoma in situ (LCIS) or lobular neoplasia: LCIS or lobular carcinoma in situ, also referred to as lobular neoplasia, is a non-invasive condition that affects the lobules, or milk-production glands, within the breast. LCIS is not considered cancer, but it is classified as a marker of elevated danger for the development of aggressive breast cancer^4,51.

1.3.6 Chest radiation therapy: Chest radiation therapy, often referred to as radiation breast therapy or chest wall, is a common treatment modality used in breast cancer management. It involves the application of high-energy X-rays or other forms of radiation to target and destroy cancer cells in the breast or the chest wall^4,52.

1.3.7 Exposure to diethylstilbesterol (DES): Diethylstilbesterol (DES) is a synthetic form of estrogen that was prescribed to pregnant women within the mid-20^th century to prevent miscarriages and complications while becoming pregnancy was associations during pregnancy. Unfortunately, it was later discovered that DES explored while pregnancy was as connected with various health risks, including a higher chance of certain health conditions between DES exposure and the likelihood of developing breast cancer is not as clear-cut as some other health risks associated with DES^4,53.

1.3.8 Lifestyle and Personal Behavior-Related Risk Factors of Breast Cancer: A person's personal conduct and way of life can have an impact on their risk of breast cancer. While these factors may not guarantee the emergence of breast cancer, making certain choices and adopting healthier behaviours can help reduce the risk^4,54.

1.3.9 Birth control and contraceptives: Research has shown that the use of birth control pills or oral contraceptives, may marginally raise the risk of breast cancer, particularly in current or recent users. However, this increased risk appears to diminish after discontinuing their use, and the overall risk remains relatively low. It's crucial to remember that other factors like age, family history and lifestyle, may potentially impact breast cancer^4,55.

1.3.10 Hormone replacement therapy (HRT) after menopause: Hormone replacement therapy (HRT), referred as menopausal hormone therapy, involves the application of hormones, typically estrogen and progestin (in combined HRT) or estrogen alone (in estrogen replacement therapy), to alleviate the symptoms of menopause. While HRT can be effective in managing symptoms complex and controversial issue^4,56.

1.3.11 Excessive alcohol consumption: Abnormally high intake of alcohol is a well-established hazard for several cancer kinds, among them breast cancer. While moderate alcohol consumption may have some cardiovascular benefits, excessive or heavy drinking can make breast cancer more likely^4,57.

1.3.12 Significant overweight or obese: Being significantly overweight or obese is a known risk factor for breast cancer and can impact many facts of breast cancer management and outcomes^4,58.

1.3.13 Not having children or not breastfeeding: Breast cancer risk can be influenced by nursing or not having children, although the connection between these variables, and breast cancer is complex and can vary among individuals^4,59.

1.3.13 Early onset of menstruation or cessation of menopause after age 55: Both starting menstruation in their early years (early menarche) and experiencing menopause following 55 years of age (late menopause) are linked to a higher chance of developing breast cancer, particularly hormone receptor-positive (ER-positive) breast cancer^4,60.

1.3.14 Lack of physical activity: Absence of physical exercise is a well-recognised risk factor for various health conditions, including breast cancer. Engaging in regular physical activity has numerous health benefits and can contribute to a reduced the possibility within breast cancer^4,61,62.

Figure 2: Symptoms of Breast Cancer

1.4 Breast cancer types:

Common breast cancers can be categorized into three main classes based on invasiveness and pathological features: invasive, metastatic and non-invasive (or in situ) breast cancers.

1.4.1 In situ, or non-invasive, breast cancer Intraductal carcinoma, commonly known as ductal carcinoma in situ (DCIS): DCIS, or ductal carcinoma in, referred as intraductal carcinoma, is a non-invasive breast cancer which originates in the ducts that milk within the breast. As opposed to aggressive breast cancer, which has the capacity to disseminate to nearby tissues, DCIS is confined to the ducts that milk and has not invaded the tissue around the breasts^4,45.

1.4.2 Invasive or infiltrating breast cancer:

· Invasive Ductal Carcinoma (IDC): Invasive Ductal Carcinoma (IDC), also known as Infiltrating Ductal Carcinoma, is the most common type breast cancer, which is responsible for around 70-80% of every diagnosed breast cancer. IDC begins in the ducts that milk within the breast and then invades the around the tissue within the breast^1,4,63.

· Invasive Lobular Carcinoma (ILC): Invasive Lobular Carcinoma (ILC), also known as Infiltrating Lobular Carcinoma, one kind of breast cancer that originates in the lobules within the breast. It accounts for 10-15% of all invasive breast cancers. ILC is characterized by its distinct histological features and clinical behaviour^1,64.

1.4.3 Metastatic breast cancer: Stage IV breast cancer is another name for metastatic breast cancer or advanced breast cancer, one kind of breast cancer that has spread from the breast to different body areas. Breast cancer with metastases is taken into the most advanced stage for breast cancer and is typically not curable. However, it frequently be managed and treated to help control symptoms, improve standard of living, and extend survival^4,65.

1.4.4 Common types of breast cancer:

1.4.4.1 Inflammatory breast cancer (IBC): Breast cancer caused by inflammation is not often and aggressive kind among cancer in the breasts. It represents between 1 to 5% of every case of breast cancer. Unlike other forms among breast cancer, IBC typically is absent as a distinct lump or tumour. Instead, it manifests with symptoms that resemble an inflammation or infection inside the breast^4,43.

1.4.4.2 Breast cancers among men and children & adolescents: While breast cancer is more commonly associated with women, it can also occur in men and, although rare, among children and adolescents^4,44.

1.4.4.3 Paget disease of the breast: The Paget's illness of the breast, also known as the disease Paget's of the nipple, is an uncommon kind among breast cancer that affects the nipple and areola's skin. It bears Sir James Paget's name, the British surgeon who first described the condition in 1874^4,45.

1.4.4.4 Papillary carcinoma: A kind of cancer called papillary carcinoma that can occur in various organs, including the breast, thyroid, kidney, and bladder. In relation to breast cancer, papillary carcinoma refers to a specific subtype of breast cancer is distinguished by the presence of papillary structures within the tumour^4,63.

1.4.4.5 Phyllodes tumour: Phyllodes tumour, also known as osteosarcoma phyllodes, is a unusual kind of breast tumour that develops in the connective tissue (stroma) inside the breast. Unlike more common breast tumours like ductal carcinoma or lobular carcinoma, phyllodes tumours arise from the stromal cells instead of the glandular cells^4,64.

1.4.4.6 Angiosarcoma of the breast: Angiosarcoma among the breast is an uncommon and severe form of cancer that originates from the cells that border the blood vessels or lymphatic vessels inside the tissue among the breast. It constitutes less than 1% of every breast cancer. Angiosarcoma can occur within the breast as a primary tumour or as a secondary tumour following radiation therapy for a previous breast cancer^4,65.

2. Molecular or intrinsic subtypes of breast cancer:

2.1 Luminal A breast cancer: Luminal A breast cancer is a kind of the disease that is characterized by the specific molecular and genetic features of the tumour cells. It falls under the broader category of hormone receptor-positive (HR+) breast cancers. Luminal A breast cancer tends to have a more favourable prognosis compared to other subtypes, such as luminal B, HER2-positive, or triple-negative breast cancer^4,14.

2.2 Luminal B breast cancer: Luminal B Cancer of the breast is one of the subtypes among breast cancer which falls under the broader category of hormone receptor-positive (HR+) breast cancers. It is characterized by specific molecular and genetic features of the tumour cells. Luminal B breast cancer is considered more aggressive than luminal A breast cancer and might be more dangerous recurrence^4,14.

2.3 HER2-enriched breast cancer: HER2-enriched is the causes among breast cancer described by the overexpression or amplification of the gene that codes for the human epidermal growth factor receptor 2 (HER2). This particular form of breast cancer is linked to more aggressive tumour behaviour with an increased chance of recurrence compared to other subtypes. However, targeted therapies that specifically inhibit the HER2 protein have significantly improved outcomes for patients with HER2-enriched breast cancer^4,15.

2.4 Triple-negative/basal-like breast cancer (TNBC): Tripal-negative breast cancer (TNBC) is a kind of breast cancer is distinguished by the lack of these specific receptors commonly found on the surface among breast cancer cells, the human epidermal growth factor receptor 2 (HER2), the progesterone receptor, and the estrogen receptor (ER). TNBC is so named because it lacks representation of these three receptors, making it distinct from various forms of breast cancer. Approximately 10-20% of all cases included among breast cancer are classified as TNBC^{4,6,10,12,13,24}.

2.5 Normal-like breast cancer: Normal-like One kind of breast cancer that is relatively rare and has distinct characteristics when in contrast to other kinds of breast cancer. It is called “normal-like” because the patterns of gene expression in the cancer cells in this subtype ones that are similar to normal breast tissue more closely than other subtypes of cancer of the breast⁴.

Figure 3: A list of the intrinsic or molecular forms of breast cancer

3. Molecular Mechanism:

A steroid hormone estrogen binds to two different types of receptors in the body to control a variety of physiological activities. The nuclear hormone receptor superfamily comprises transcription regulators and the ERα and ERβ estrogen receptors' structures are made up of different functional domains²⁹. ERα which is the ESR1 gene encodes it. and is found on chromosome 6 at locus 6q25.1 has a molecular mass of 67 kDa and 595 amino acids while ERβ is made up of 530 amino acids and is the ESR1 gene encodes it which is found on chromosome 14 (14q23–24)³⁰. The primary distinction between the two proteins is that ERβ's amino-terminal domain is shorter than ERα's. Another is a transmembrane receptor known as GPER which has structural similarities with a conventional G protein-coupled receptor in that it consists of seven transmembrane α-helical regions, four cytosolic segments, four extracellular segments and GPER is encoded by the GPER1 gene which is found at 7p22.3, locus on chromosome 7^3,4,31.

3.1 Genomic pathway

The receptors for nuclear estrogen that are ERα and ERβ function as ligand-activated transcription factors in the mechanism of estrogen signalling. Before estrogen binds to each of their receptors ERα and ERβ are inactive. However, when estrogen crosses the membrane of the plasma and interacts or binds with ERα and ERβ within the cytoplasm it causes the receptors to change conformation including dimerization and then becomes activated allowing it to directly affect DNA sequences. After translocating into the nucleus these complex attaches to or interacts with enhancer regions of target gene promoters which are transcriptional coactivators known as estrogen-responsive elements (EREs)³². When estrogen is activated through its interaction with GPER1, ERα and ERβ, intracellular signalling cascades occur. Estrogen-mediated signalling events can be classified as either genomic or non-genomic due to the variations in both molecular and cellular processes that might result in the regulation of gene expression. These processes involve the direct or indirect binding of estrogen-receptor complexes to DNA. Genomic effects include direct contact with chromatin at certain DNA stretches known as estrogen response elements (EREs) and migration of the estrogen-receptor complexes to the cell nucleus³³. Additionally, ERα regulates genes not having ERE in their advocates by interacting with transcription factors via serum-responsive elements (SREs), like specific protein 1(SP1) and activator protein 1 (AP1). Thus, this genomic activity controls hundreds of target genes involved in transcription that are necessary for cell division and proliferation³⁴. As a result, most breast tumors classified as luminal or ERα+ are developed as a result of the dysregulation of the expression activity of ERα or its target and coregulators genes. It's important to remember that estrogen can activate the two additional receptors ERβ and GPER. Generated through the ESR2 gene, nucleus receptor type ERβ that shares a structure with ERα and is similar to Erα^,4,35.

3.2 Non-genomic pathway

Several research investigations have been conducted on the connection between signaling from sex steroids (androgen or estrogen) and growth factors like IGF or EGF. This entails the prompt intracellular signaling pathways activated, including the synthesis of cAMP (cyclic adenosine monophosphate) or the initiation of receptors for growth factors PI3K/AKT or Ras/MAPK pathways. The MAPK route is triggered when E2 binds to ERα and creates a compound in the cytoplasm with many proteins including the PI3K subunit p85 and Src protein kinase. GPER is a type of protein with seven transmembrane domains that can quickly activate cellular responses to estrogen³⁶. It's found in various organs including the liver, adipose tissue and mammary gland. GPER is also found in various types of cells that cause breast cancer. When GPER is stimulated by estrogen, shown to activate ERK1/2 phosphorylation through Gb, the transactivation with relation to the epidermal growth factor receptor (EGFR) depends on G, it raises cAMP levels, mobilizes intracellular calcium and protein/lipid kinases (i.e., PKC and PKA). This leads to activating signalling pathways like PI3K/AKT and Ras/MAPK that regulate gene transcription for cell survival and growth. These genes include c-Fos, cJun, ERK1 and SP1 which promote protein expression, apoptosis, cell proliferation, cell migration and growth by regulating the cycle of cells³⁷. Various signaling pathways, including phosphoinositide 3-kinases/protein kinase B (PI3K/AKT) and mitogen-activated protein kinases (Ras/MAPK) are triggered when the receptor for HER2 is overexpressed. The formation of metastases is encouraged by this increased cell endurance as well as proliferation. Compared to luminal tumors this kind among breast cancer is therefore more aggressive. Increased tyrosine kinases receptor expression or activation and associated signalling routes like the HER2 or EGFR1 families is a common observation. These compounds activate an assortment of signalling routes such PI3K/AKT, Ras/MAPK, and PLC/PKC that regulate cell division and survival³⁸. One specific element that leads the overexpression of is linked to the development of breast cancer to HER2 and EGFR1. However, the Insulin-like Growth Factor 1 Receptor (IGF1R) binds the IGF1 protein which is necessary for the growth and operation of the mammary gland. When IGF1 binds to its receptor IGF1R becomes phosphorylated. This activation then triggers the Ras/MAPK and PI3K/AKT signalling pathways. These pathways have both anti-apoptotic and proliferative properties³⁹. Breast cancer cells may multiply and survive uncontrollably if these pathways are overactivated. This could be due to either IGF1R overexpression or high blood levels of IGF1. Furthermore, the absence of BRCA1 and BRCA2 tumour suppressor gene expression or function might have a role in the development of breast tissue cancer. These DNAs generate the homologous recombination-repairing proteins that repair DNA double-strand breaks. These DNA repair mechanisms can be changed by mutations in these genes which elevates the possibility of getting mutations. Consequently, this leads to an increase in various cancers particularly ovarian and breast cancers⁴⁰.

In many model systems E2 immediately activates MAPK however the exact mechanisms underlying this are still up for debate. MAPK is activated via a pathway mediated by Shc by a variety of growth factor receptors on the cell membrane such as those for IGF, nerve growth factor, platelet-derived growth factor and epidermal growth factor. The non-genomic activities of estrogen often entail the modulation of cAMP the activation of signalling cascades by protein kinase that indirectly alters gene expression and the activation of signal-transduction pathways that generate intracellular second messengers⁴¹. Protein-kinase cascades can be categorized into four primary groups: Four distinct signalling pathways exist: There are four pathways that involve phospholipase C (PLC) and protein kinase C (PKCs); Ras/Raf/MAPK cascade; phosphatidyl inositol 3 kinase (PI3K) and Akt kinase cascade; and cAMP/protein kinase A (PKA) pathway. Another benefit of GPER1 binding to estrogen is the stimulation of adenylyl cyclase and the estrogen-dependent stimulation of the receptor for epidermal growth factor (EGFR). When transcription factors are phosphorylated by the previously stated protein kinases, their function and ability to bind to genomic regions to control the expression of genes can alter. Transcription factors including Elk-1, CREB, the NF-κB complex, CCAAT-enhancer-binding protein beta (C/EBPβ) and the signal transducer and activator of the transcription (STAT) family can be affected by these signaling pathways⁴².

Figure 4: Major signalling pathways that contribute to the onset and spread of breast cancer

The G protein-coupled estrogen receptor (GPER) is mediated by intracellular cAMP-protein kinase (PK) and phosphorylation of cAMP-response element-binding protein (CREB). Specifically, initiation of the RTK pathway by EGF or IGF1 triggers signalling pathways including Ras/MAPK/ERK or PI3K/AKT/mTOR which in turn trigger transcription factors involved in cell fate determination. The progesterone receptor (PR) pathway and estrogen receptor (ER) pathway also serve as transcription-related factors upon homo-or heterodimers. PTEN prevents PIP2 phosphorylation which is required for PI3K to activate AKT so MAPK stands for mitogen-activated protein kinase pathways. Protein kinase B (AKT), mTOR (mammalian target of rapamycin), PI3K (phosphoinositide 3-kinase), PIP (phosphatidylinositol phosphate); PKC (protein kinase C), PLC (phospholipase C), AKT (protein kinase B), NFκB (nucleus κ-light-chain-enhancer of activated B cells), MAPK/Erk kinase 1/2 is known as MEK1/2 and extracellular signal-regulated kinase 1/2 is known as ERK1/2. (Biorender)

4. Challenges during breast cancer:

Most of the main challenges emerging from the healthcare demand worldwide regard long-term care of chronic conditions. Diseases once lethal are today treatable, but still deeply impact patients’ and survivors’ quality of life and require continual health management even after recovery. For example, breast cancer patients and survivors have to deal with important challenges daily. Some of them are common in chronic health conditions, while other experiential issues are specific to this disease^2,17.

An important issue in chronic disease is emotional distress; the American Psychiatric Association recognized diagnosis, such as cancer, as a traumatic stressor possibly generating impairment in different areas of functioning (ability to work and social relationships) because of negative cognitions and mood. Usually, patients react to the disease onset and management in different ways and they may develop depression and anxiety. Patients often experience anxiety because of the anticipation of negative outcomes and uncertainty about the future. Two groups of factors contribute to anxiety: physical (e.g., age, hormonal changes, side effects of treatment), and psychological (e.g., negative feelings about the disease, and the resistance to change one’s lifestyle to adhere to treatment prescriptions)¹⁷.

5. Treatment strategies: TNBCs are a heterogeneous and aggressive form of cancer, for which there are no scientifically validated biologically targeted effective treatments. The lack of ERs, PRs, and HER2 makes finding a reliable treatment alternative for TNBC extremely difficult^11,13.

Figure 5: Breast cancer management approaches

Surgery and radiotherapy: Radiation therapy is frequently administered following surgery for the treatment of early-stage breast cancer. Radiation therapy is used to eradicate any cancer cells that could still be present after surgery, while surgery is used to remove the malignancy. This reduces the possibility of the cancer returning (recurrence).

Chemotherapy: One popular treatment for breast cancer is chemotherapy. It kills cancer cells with anti-cancer (cytotoxic) medications. The medications are transported via the bloodstream throughout the body. They function by preventing cancer cells from proliferating.

Targeted therapy: Targeted drug therapy involves administering medications that specifically target proteins on breast cancer cells which promote their growth, metastasis, and prolonged survival. Drugs that target cancer cells either kill the cells or stop them from growing. They don’t have the same adverse effects as chemotherapy.

Certain medications used in targeted therapy, including monoclonal antibodies, have several functions in regulating cancer cells and can also be classified as immunotherapy due to their immune-stimulating properties.

These medications are effective against cancers that have spread to distant parts of the body because, like chemotherapy, they enter the bloodstream and virtually every part of the body is affected. Sometimes targeted medication’s function while chemotherapy medications don't.

6. Herbal treatment

It's crucial to remember that there is no proven herbal treatment for breast cancer that can replace conventional medical treatments such as surgery, chemotherapy, radiation therapy, and targeted therapies. Breast cancer is a serious disease, and it’s crucial to consult with a qualified medical professional to discuss your treatment options and make informed decisions about your care^11,20,21.

However, some herbal remedies as complementary therapies to manage adverse consequences of cancer therapy, improve their overall well-being, and support their immune system. It’s essential to discuss any complementary therapies with your healthcare team to ensure they do not interfere with your prescribed treatments and are safe for your specific situation^20,21.

These are a few herbal remedies that are sometimes utilised in a complimentary therapy in cases of breast cancer care:

1. Herbal teas: Certain herbal teas like green tea and chamomile tea are believed to have antioxidant properties that may help support overall health and reduce inflammation.

2. Turmeric: Curcumin, a compound found in turmeric, has anti-inflammatory properties and could be applied as a dietary supplement. Some studies suggest it may have potential health benefits, but more research is needed.

3. Ginger: Ginger is sometimes used to help alleviate nausea and vomiting, which can be side effects of chemotherapy.

4. Mistletoe: Extracts from mistletoe have been used in some complementary cancer therapies. However, scientific evidence supporting its effectiveness is limited, and it is only meant to be utilized under the guidance of a qualified practitioner.

Maitake and Shiitake Mushrooms: Some mushrooms are believed to have immune-boosting properties. Again, use these under the guidance of a healthcare provider.

7. CONCLUSION:

Cancer of the breast is a complicated disease that involves genetic, epigenetic, and environmental factors in its manifestation. The most common inherited genetic factor is known, but there are also epidemiological aspects and risk variables connected to occurrences of breast cancer around the world. Cancer of the breast is prevalent worldwide and is one of the main causes of mortality among women. Interestingly, breast cancer mortality rates tend to be higher in less developed countries.

Multi-factorial elements contribute to the growth of breast cancer, with many factors acting independently or in combination, particularly in high-risk individuals. Understanding the etiology of this prevalent disease, which if not found early, is linked to significant mortality and morbidity. Therefore, early screening for high-risk individuals and appropriate monitoring of treatment to identify recurrence in its early phases is highly recommended.

8. ACKNOWLEDGEMENT:

The authors are grateful to the Institute of Pharmaceutical Science, Guru Ghasidas Vishwavidyalaya University for cooperation and for providing institutional facilities. We offer our sincere appreciation for the learning opportunities provided by our institution.

9. REFERENCES:

1. Giaquinto AN, Sung H, Miller KD, Kramer JL, Newman LA, Minihan A, Jemal A, Siegel RL. Breast cancer statistics, 2022. CA: A Cancer Journal for Clinicians. 2022 Nov; 72(6):524-41.

2. Fortner BV, Stepanski EJ, Wang SC, Kasprowicz S, Durrence HH. Sleep and quality of life in breast cancer patients. Journal of Pain and Symptom Management. 2002 Nov 1;24(5):471-80.

3. Goff SL, Danforth DN. The role of immune cells in breast tissue and immunotherapy for the treatment of breast cancer. Clinical Breast Cancer. 2021 Feb 1;21(1): e63-73.

4. Feng Y, Spezia M, Huang S, Yuan C, Zeng Z, Zhang L, Ji X, Liu W, Huang B, Luo W, Liu B. Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes & Diseases. 2018 Jun 1;5(2):77-106.

5. Baksh M, Mahajan B, Dufresne MM, Shoukry MM, Nussbaum S, Abbaszadeh-Kasbi A, Ashary M, Vandenberg J, Gabriel EM. Circulating tumor DNA for breast cancer: Review of active clinical trials. Cancer Treatment and Research Communications. 2022 Jul 12:100609.

6. Barzaman K, Karami J, Zarei Z, Hosseinzadeh A, Kazemi MH, Moradi-Kalbolandi S, Safari E, Farahmand L. Breast cancer: Biology, biomarkers, and treatments. International Immunopharmacology. 2020 Jul 1; 84:106535.

7. Ruiz-Casado A, Alvarez-Bustos A, de Pedro CG, Mendez-Otero M, Romero-Elias M. Cancer-related fatigue in breast cancer survivors: a review. Clinical Breast Cancer. 2021 Feb 1;21(1):10-25.

8. Moshina N, Falk RS, Hofvind S. Long-term quality of life among breast cancer survivors eligible for screening at diagnosis: a systematic review and meta-analysis. Public Health. 2021 Oct 1; 199:65-76.

9. Momenimovahed Z, Salehiniya H. Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer: Targets and Therapy. 2019 Apr 10:151-64.

10. Wu HT, Lin J, Liu YE, Chen HF, Hsu KW, Lin SH, Peng KY, Lin KJ, Hsieh CC, Chen DR. Luteolin suppresses androgen receptor-positive triple-negative breast cancer cell proliferation and metastasis by epigenetic regulation of MMP9 expression via the AKT/mTOR signaling pathway. Phytomedicine. 2021 Jan 1; 81:153437.

11. Wang X, Yang Y, A Y, Fang G. The mechanism of anticancer action and potential clinical use of kaempferol in the treatment of breast cancer. Biomedicine & Pharmacotherapy. 2019 Sep 1; 117:109086.

12. Farghadani R, Naidu R. The anticancer mechanism of action of selected polyphenols in triple-negative breast cancer (TNBC). Biomedicine & Pharmacotherapy. 2023 Sep 1; 165:115170.

13. Maqbool M, Bekele F, Fekadu G. Treatment strategies against triple-negative breast cancer: an updated review. Breast Cancer: Targets and Therapy. 2022 Jan 11:15-24.

14. Mehanna J, Haddad FG, Eid R, Lambertini M, Kourie HR. Triple-negative breast cancer: current perspective on the evolving therapeutic landscape. International Journal of Women's Health. 2019 Jul 31:431-7.

15. Sukumar J, Gast K, Quiroga D, Lustberg M, Williams N. Triple-negative breast cancer: Promising prognostic biomarkers currently in development. Expert Review of Anticancer Therapy. 2021 Feb 1;21(2):135-48.

16. Bodewes FT, van Asselt AA, Dorrius MD, Greuter MJ, de Bock GH. Mammographic breast density and the risk of breast cancer: A systematic review and meta-analysis. The Breast. 2022 Sep 26.

17. Triberti S, Savioni L, Sebri V, Pravettoni G. eHealth for improving quality of life in breast cancer patients: a systematic review. Cancer Treatment Reviews. 2019 Mar 1; 74:1-4.

18. Venetis K, Invernizzi M, Sajjadi E, Curigliano G, Fusco N. Cellular immunotherapy in breast cancer: The quest for consistent biomarkers. Cancer Treatment Reviews. 2020 Nov 1; 90:102089.

19. Moragon S, Di Liello R, Bermejo B, Hernando C, Olcina E, Chirivella I, Lluch A, Cejalvo JM, Martínez MT. Fertility and breast cancer: A literature review of counseling, preservation options and outcomes. Critical Reviews in Oncology/Hematology. 2021 Oct 1; 166:103461.

20. Shareef M, Ashraf MA, Sarfraz M. Natural cures for breast cancer treatment. Saudi Pharmaceutical Journal. 2016 May 1;24(3):233-40.

21. Kim W, Lee WB, Lee JW, Min BI, Baek SK, Lee HS, Cho SH. Traditional herbal medicine as adjunctive therapy for breast cancer: A systematic review. Complementary Therapies in Medicine. 2015 Aug 1;23(4):626-32.

22. Richie RC, Swanson JO. Breast cancer: a review of the literature. Journal of Insurance Medicine-New York Then Denver. 2003 Jan 1;35(2):85-101.

23. Salimifard S, Masjedi A, Hojjat-Farsangi M, Ghalamfarsa G, Irandoust M, Azizi G, Mohammadi H, Keramati MR, Jadidi-Niaragh F. Cancer associated fibroblasts as novel promising therapeutic targets in breast cancer. Pathology-Research and Practice. 2020 May 1;216(5):152915.

24. Ai D, Yao J, Yang F, Huo L, Chen H, Lu W, Soto LM, Jiang M, Raso MG, Wang S, Bell D. TRPS1: a highly sensitive and specific marker for breast carcinoma, especially for triple-negative breast cancer. Modern Pathology. 2021 Apr 1;34(4):710-9.

25. Nguyen AT, Shiao SL, McArthur HL. Advances in combining radiation and immunotherapy in breast cancer. Clinical Breast Cancer. 2021 Apr 1;21(2):143-52.

26. Gupta V, Vasudev M, Doegar A, Sambyal N. Breast cancer detection from histopathology images using modified residual neural networks. Biocybernetics and Biomedical Engineering. 2021 Oct 1; 41(4):1272-87.

27. Carter SM, Rogers W, Win KT, Frazer H, Richards B, Houssami N. The ethical, legal and social implications of using artificial intelligence systems in breast cancer care. The Breast. 2020 Feb 1; 49:25-32.

28. Nascimento C, Ferreira F. Tumor microenvironment of human breast cancer, and feline mammary carcinoma as a potential study model. Biochimica et Biophysical Acta (BBA)-Reviews on Cancer. 2021 Aug 1;1876(1):188587.

29. Marino M, Galluzzo P, Ascenzi PJCg. Estrogen signaling multiple pathways to impact gene transcription. 2006;7(8):497-508.

30. Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. 1997; 138(3): 863-70.

31. Barton M, Filardo EJ, Lolait SJ, Thomas P, Maggiolini M, Prossnitz ERJTJosb, et al. Twenty years of the G protein-coupled estrogen receptor GPER: Historical and Personal Perspectives. 2018; 176: 4-15.

32. Verde G, Llobet LID, Wright RH, Quilez J, Peiró S, Dily FL, et al. Unliganded progesterone receptor governs estrogen receptor gene expression by regulating DNA methylation in breast cancer Cells. 2018; 10(10): 371.

33. Frasor J, Danes JM, Komm B, Chang KC, Lyttle CR, Katzenellenbogen BSJE. Profiling of estrogen up-and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell Phenotype. 2003;144(10):4562-74.

34. Stender JD, Kim K, Charn TH, Komm B, Chang KC, Kraus WL, et al. Genome-wide analysis of estrogen receptor α DNA binding and tethering mechanisms identifies Runx1 as a novel tethering factor in receptor-mediated transcriptional activation. 2010; 30(16): 3943-55.

35. Mal R, Magner A, David J, Datta J, Vallabhaneni M, Kassem M, et al. Estrogen receptor beta (ERβ): a ligand activated tumor suppressor. 2020;10:587386.

36. Migliaccio A, Di Domenico M, Castoria G, de Falco A, Bontempo P, Nola E, et al. Tyrosine kinase/p21ras/MAP‐kinase pathway activation by estradiol‐receptor complex in MCF‐7 cells. 1996;15(6): 1292-300.

37. Yu T, Yang G, Hou Y, Tang X, Wu C, Wu X, et al. Cytoplasmic GPER translocation in cancer-associated fibroblasts mediates cAMP/PKA/CREB/glycolytic axis to confer tumor cells with multidrug resistance. 2017;36(15):2131-45.

38. Steelman LS, Chappell WH, Akula SM, Abrams SL, Cocco L, Manzoli L, et al. Therapeutic resistance in breast cancer cells can result from deregulated EGFR signaling. 2020;78:100758.

39. Christopoulos PF, Msaouel P, Koutsilieris MJMc. The role of the insulin-like growth factor-1 system in breast cancer. 2015;14(1):1-14.

40. Venkitaraman ARJDr. How do mutations affecting the breast cancer genes BRCA1 and BRCA2 cause cancer susceptibility? 2019; 81: 102668.

41. Santen R, Song R, Zhang Z, Kumar R, Jeng M, Masamura S, et al. Adaptive hypersensitivity to estrogen: mechanism for superiority of aromatase inhibitors over selective estrogen receptor modulators for breast cancer treatment and prevention. 2003; 10(2): 111-30.

42. Picotto G, Massheimer V, Boland RJM, endocrinology c. Acute stimulation of intestinal cell calcium influx induced by 17β-estradiol via the cAMP messenger system. 1Veronesi U, Boyle P, Goldhirsch A, Orecchia R, Viale G. Breast cancer. Lancet. 2005; 365(9472): 1727-1741.

43. Collaborative Group on Hormonal Factors in Breast Cancer. Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58 209 women with breast canc. 996; 119(2): 129-34.

44. er and 101 986 women without the disease. The Lancet. 2001 Oct 27; 358(9291): 1389-99.

45. Hulka BS. Epidemiology of susceptibility to breast cancer. Progress in Clinical and Biological Research. 1996 Jan 1;395:159-74.

46. Kamińska M, Ciszewski T, Łopacka-Szatan K, Miotła P, Starosławska E. Breast cancer risk factors. Menopause Review/Przegląd Menopauzalny. 2015 Sep 30;14(3):196-202.

47. Wang J, Costantino JP, Tan-Chiu E, Wickerham DL, Paik S, Wolmark N. Lower-category benign breast disease and the risk of invasive breast cancer. Journal of the National Cancer Institute. 2004 Apr 21;96(8):616-20.

48. Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K, Vierkant RA, Maloney SD, Pankratz VS, Hillman DW, Suman VJ. Benign breast disease and the risk of breast cancer. New England Journal of Medicine. 2005 Jul 21;353(3):229-37.

49. Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. New England Journal of Medicine. 1985 Jan 17;312(3):146-51.

50. Dupont WD, Parl FF, Hartmann WH, Brinton LA, Winfield AC, Worrell JA, Schuyler PA, Plummer WD. Breast cancer risk associated with proliferative breast disease and atypical hyperplasia. Cancer. 1993 Feb 15;71(4):1258-65.

51. Singletary SE. Rating the risk factors for breast cancer. Ann Surg. 2003; 237(4): 474-482.

52. Howell A, Anderson AS, Clarke RB, Duffy SW, Evans DG, Garcia-Closas M, Gescher AJ, Key TJ, Saxton JM, Harvie MN. Risk determination and prevention of breast cancer. Breast Cancer Research. 2014 Oct; 16(5): 1-9.

53. Anothaisintawee T, Wiratkapun C, Lerdsitthichai P, Kasamesup V, Wongwaisayawan S, Srinakarin J, Hirunpat S, Woodtichartpreecha P, Boonlikit S, Teerawattananon Y, Thakkinstian A. Risk factors of breast cancer: a systematic review and meta-analysis. Asia Pacific Journal of Public Health. 2013 Sep; 25(5): 368-87.

54. Ozsoy A, Barça N, Dolek BA, Aktaş H, Elverici E, Araz L, Ozkaraoğlu O. The relationship between breast cancer and risk factors: a single-center study. European Journal of Breast Health. 2017 Jul;13(3):145.

55. McTiernan A. Behavioral risk factors in breast cancer: can risk be modified?. The Oncologist. 2003 Aug 1;8(4):326-34.

56. Vogel VG. Epidemiology, genetics, and risk evaluation of postmenopausal women at risk of breast cancer. Menopause. 2008 Jul 1;15(4):782-9.

57. Byrne C, Webb PM, Jacobs TW, Peiro G, Schnitt SJ, Connolly JL, Willett WC, Colditz GA. Alcohol consumption and incidence of benign breast disease. Cancer Epidemiology Biomarkers & Prevention. 2002 Nov 1;11(11):1369-74.

58. Patterson RE, Cadmus LA, Emond JA, Pierce JP. Physical activity, diet, adiposity and female breast cancer prognosis: a review of the epidemiologic literature. Maturitas. 2010 May 1;66(1):5-15.

59. Rock CL, Demark-Wahnefried W. Can lifestyle modification increase survival in women diagnosed with breast cancer?. The Journal of Nutrition. 2002 Nov 1;132(11):3504S-9S.

60. Yang XR, Sherman ME, Rimm DL, Lissowska J, Brinton LA, Peplonska B, Hewitt SM, Anderson WF, Szeszenia-Dabrowska N, Bardin-Mikolajczak A, Zatonski W. Differences in risk factors for breast cancer molecular subtypes in a population-based study. Cancer Epidemiology Biomarkers & Prevention. 2007 Mar 1;16(3):439-43.

61. Barnard ME, Boeke CE, Tamimi RM. Established breast cancer risk factors and risk of intrinsic tumor subtypes. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer. 2015 Aug 1;1856(1):73-85.

62. Anderson WF, Rosenberg PS, Prat A, Perou CM, Sherman ME. How many etiological subtypes of breast cancer: two, three, four, or more?. Journal of the National Cancer Institute. 2014 Aug 1;106(8):dju165.

63. Colditz GA, Kaphingst KA, Hankinson SE, Rosner B. Family history and risk of breast cancer: nurses’ health study. Breast Cancer Research and Treatment. 2012 Jun;133:1097-104.

64. Polyak K. Breast cancer: origins and evolution. The Journal of Clinical Investigation. 2007 Nov 1;117(11):3155-63.

65. Allison KH. Molecular pathology of breast cancer: what a pathologist needs to know. American Journal of Clinical Pathology. 2012 Dec 1;138(6):770-80.

Received on 08.11.2024 Revised on 17.02.2025

Accepted on 24.04.2025 Published on 01.07.2025

Available online from July 05, 2025

Research J. Pharmacy and Technology. 2025;18(7):3374-3384.

DOI: 10.52711/0974-360X.2025.00488

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