New Shining Stars in The Sky of Breast Cancer Diagnosis and Prognosis:

A Review

 

Nahla E. EL-Ashmawy1, Enas A. EL-Zamarany2, Naglaa F. Khedr1, Hend M. Selim1,

Eman G. Khedr1

1Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt.

2Clinical Pathology Department, Faculty of Medicine, Tanta University, Egypt.

*Corresponding Author E-mail: hendmselim@gmail.com, hend.m.selim@pharm.tanta.edu.eg

 

ABSTRACT:

Breast cancer is one of the most prevalence cancer that hits women around the world and the second cause of death among different cancer types. Breast cancer is heterogeneous and combines various subtypes and classes that makes the diagnosis and treatment a complicated issue. Thus, many efforts were done regarding discovering new biomarkers that help in early diagnosis, prognosis, treatment, which lead to better outcome along with enhancing survival rate. This review aimed to gather, concisely and briefly, some of the most recent discovered genes and proteins with high potential to be used as biomarkers for breast cancer detection and prognosis. We discussed, briefly, the promising role of tissue Lipocalin 1, Cysteine protease cathepsin, Ras associated proteins 22a, 4-Heterogeneity nuclear proteins A2/B1, 6-Insulinoma associated protein 1, 7- Fizzy-related protein 1 and Facio-genital dysplasia gene 3, in addition to serum Autotaxin –Lysophosphatidic acid in breast cancer diagnosis and prognosis.

 

KEYWORDS: Breast cancer, New, Biomarkers, Diagnosis, Prognosis.

 

 


INTRODUCTION:

Breast cancer is one of the most common cancer in women worldwide, with an increasing incidence rate. It is a heterogeneous type of cancer with many underlying risk factors including: sex hormones, menopause, age, family history, increased body mass index and hormonal replacement therapy1,2,3,4,5,6,7.

 

According to ATCC 7th edition depending on human epidermal growth factor receptor 2 (HER2) expression, estrogen and progesterone receptor expression, breast cancer is mainly classified into: luminal A, luminal B, triple negative and HER2 positive.8 Histologically, breast cancer is classified into insitu and invasive under which there are many subtypes1

 

Despite the advances in treatment and improvement of the overall survival in the recent years, there is still challenges regarding the early detection and prognosis as well as the extent of disease at the time of detection is highly related to the prognosis9,10,11. Thus, finding new diagnostic and prognostic biomarkers could play a vital role in the early detection and hence improve quality of life and treatment outcomes12,13. In this review, we summarize, some promising novel biomarkers mentioned in recent international studies. The discussed biomarkers vary from proteins to genes and transcription factors, either circulating in blood or located in breast tissue (Figure 1).

 

Tissue located biomarkers:

Lipocalin 1:

Lipocalin 1, also known as tear lipocalin, is mainly found in tears and identified in many glands including lingual, salivary, nasal, lachrymal, sweat and mammary glands14,15. Lipocalin 1 retains the ability to bind with many hydrophobic molecules such as retinol, cholesterol, fatty acids and fatty alcohol and can scavenge other harmful peroxidation products16. It has been identified in many diseases including open angle glaucoma, diabetic retinopathy and Meibomian gland disease17,18.

 

Figure:1 Classification and location of promising biomarkers for breast cancer diagnosis and prognosis

 

Lipocalin 1 is expressed in obese breast cancer patients with high Body mass index19. Obese patients mainly show hyperlipidemia, thus, lipocalin 1 may be associated with hyperlipidemia, which increase the potential to experience breast cancer18. Recently, by analyzing the data of more than 1000 breast cancer patients in cancer genome atlas, it was found that lipocalin 1 is highly correlated with breast cancer progression especially in stage IV. Moreover, it is highly expressed and significantly correlated with HER2 negative, ER negative and infiltrating ductal carcinoma18. Interestingly, Lipocalin is shown to be an independent predictor of poor survival19.

 

Another previous study was conducted using bioinformatics to investigate the relevance of lipocalin 1 with breast cancer patients of different races. As mentioned in the study, lipocalin 1 expression is gradually increased between stage1 and 4 breast cancer and the protein is highly expressed in pre- and post-menopausal women. After analyzing the prognostic value, it was shown that low lipocalin 1 expression correlated with poor prognosis for relapse-free survival in all types of breast cancer, overall survival in luminal B, and post progression survival in luminal A cases20. Altogether, lipocalin 1 may act as a new promising biomarker for the breast cancer diagnosis and prognosis.

 

Cysteine protease cathepsin:

Cysteine protease cathepsin S (CTSS) is one of the cathepsin protease family which include about 11 members [21]. Cathepsin S is highly restricted to macrophage and lymphoid. It has been distinguished as a marker of prognostic value in different types of cancers such as prostate, gastric and hepatic cancer, where it indicates poor prognosis22,23,24.

 

Researchers founded that serum CTSS is expressed in women with high risk for developing breast cancer25. The Knock-down of CTSS using siRNAs resulted in suppression of MDA-MB-231 cell proliferation and invasion, which was similarly observed with pharmacological inhibitors. Moreover, CTSS inhibition decreases the aggressiveness of cancer progression, and enhance the stability of BRCA1 gene that activates DNA double strand break repair26,27,28, and combining CTSS inhibitors with chemotherapies showed a synergistic effect and enhanced the survival rate29,30.

 

In breast cancer patients a little is known about CTSS. Upon exanimating the clinical significance of stromal and epithelial CTSS expression in breast cancer patients, CTSS stromal expression was found to be correlated with bad outcome, while epithelial expression was correlated with good outcome. In patients with triple negative breast cancer; the epithelial CTSS was indicator for good prognosis which was in line with its role in patients with HER2+ breast cancer. Moreover, patients with high CTSS showed decreased lymphovascular invasion and node scoring. In infiltrating cells, CTSS was highly expressed and correlated with bad outcome, which was adherent with previous studies that explained the high CTSS expression as a result of increasing tumor associated macrophages31.

 

Ras-related protein in brain 22a:

Ras-related protein in brain 22a (Rab22a) is a member of Ras oncogene family. The function of Rab22a is mainly regulated by proteins cycling between the GDP-inactive and GTP-active states32,33. Rab22a mainly control the trafficking of recycling endosome comprising clathrin-dependent factors including glucose transporter 4, epidermal growth factor receptor and clathrin–independent factors such as β1 integrin receptor. Rab22a dysregulation is detected in many cancerous cells, since defective trafficking of growth factor receptor is considered as a main hallmark of cancer34,35.

 

In breast cancer, Rab22a is mediated in the proliferation, invasion and metastasis of breast cancer cells and correlated with poor survival rate36,37,38. Also, Rab22a mediates the formation of microvesicles which accelerate the invasion and activate metastasis process, resulting in decreasing the overall and metastatic-free survival rate in animal models and patients39.

 

In a recent study, breast cancer tissues were extracted from patients with stage 1, 2 and 3. Correlation analysis between Rab22a and clinico-pathological features was studied and Rab22a was strongly positive correlated with age of menarche, N staging, nibble invasion, T classification, venous invasion and clinical stage9 Moreover, knocking down the Rab22a gene decreased progression and invasion in vivo and in vitro cancer cells 9. These findings highlight the expression of Rab22a as a marker for poor prognosis that may help in early detection and better outcomes in patients with breast cancer.

 

Heterogeneity nuclear proteins A2/B1:

Heterogeneity nuclear proteins (hnRNP) is a large family of RNA binding proteins that play a role in telomerase maintenance, DNA repair, splicing of primary transcript and translational control. hnRNP A2/B1 is a crucial member of this family which is encoded by gene on p15 human chromosome. Since hnRNP A2/B1 is involved in splicing of pre-mRNA and translational regulation of mRNA, it participates in many physiological and pathological conditions40,41. hnRNP A2 is expressed in rheumatoid arthritis disease and can play a regulatory role in DNA replication and transcription42. By regulating the genome stability, cell cycle transition and apoptosis, hnRNP B1 is included in many diseases including cancer43.

 

hnRNP A2/B1 is isolated from breast cancer tissue and found to be positively correlated with ER expression and metastasis44,45. Recently, it was proven that hnRNP A2/B1 is overexpressed in breast cancer tissues than normal ones and silencing hnRNP A2/B1 gene has resulted in a decrease of cancer cell proliferation rate46.

 

Researchers also studied the potential of choosing hnRNP A2/B1 as biomarker for breast cancer. The nuclear and cytoplasmic expression of hnRNP A2/B1 is significantly higher in breast cancer tissues compared with normal tissue samples in patients with stage 2 and 3. Bioinformatics analysis showed a negative correlation between hnRNP A2/B1 and both overall and disease specific survival rate47. Thus, hnRNP A2/B1 could be targeted as promising prognostic biomarker and a therapeutic target for breast cancer.

 

Insulinoma associated protein 1:

Insulinoma associated protein 1 (INSM1) is a zinc finger transcription factor, found in the nervous system and neuroendocrine tissues. It has been used recently as an immuno-histochemical marker for neuro endocrine differentiation48,49. INSM1 is distinguished as a reliable neuroendocrine marker in tumors with neuroendocrine nature in lung, skin and prostate50,51,52. It is common to see neuroendocrine markers in cellular type B and mucinous and solid papillary carcinomas53.

 

The expression of neuroendocrine markers is used recently by World Health Organization to distinguish the neuroendocrine tumors, which are subsequently classified into three main groups; poorly, moderate and well differentiated neuroendocrine, and reported to have high sensitivity which may nominate it as potential marker for invasive breast cancer with neuroendocrine differentiation that counts for 30% of classifie invasive breast cancer (IBC) cases53,54.

 

The micro array analysis of samples with IBC and the immunohistochemical tests were used to examine the expression of INSM1 along with the well-known markers: chromogranin, CD56 and synaptophysin. Interestingly, INSM1 was similar with synaptophysin and chromogranin in clinicopathological and biomarker profile. INSM1 was more sensitive than both CD56 and chromogranin but less sensitive than synaptophysin and positively correlated with hormonal receptor positive IBC49.

 

Being positively expressed in some neuroendocrine breast carcinoma that don’t express synaptophysin and chromogranin, INSM1 could be used as a new favorable prognostic biomarker in detecting additional cases49,55. Another study speculated the potential of considering INSM1 as diagnostic biomarker for solid papillary carcinoma of the breast56.

 

Fizzy-related protein 1:

Fizzy-related protein 1 (FZR1), is a protein that acts as co-activator of anaphase promoting complex (APC), an E3 ubiquitin ligase complex regulating cell cycle. In the early G1 phase FZR1 is associated with APC complex and affect the phase fate decision57. When FZR1 is inactivated by cyclin dependent kinase 1 (CDK1) dependent phosphorylation, it permits the cells transition from G1 to S and G2 phase. On the other hand, the active dephosphorylated FZR1 form is achieved by the in active non phosphorylated CDK 158,59. Notably, FZR1 is essential for phosphorylation and activation of P53. Moreover, FZR1 enhanced the cell division arrest of T-47D cell line. Also, FZR1 is a negative regulator of mitogen activated protein kinase kinase/ERK oncogenic pathway involved in many cancer types progression59,60.

 

The knockdown of FZR1 affects cell division arrest induced by palbociclib treatment in human breast cancer 61. In an interesting study on the possibility of considering FZR1 as biomarker for breast cancer progression, it was found that FZR1 modulated and enhanced apoptosis through stabilizing P53 via impairing Serine-15 site phosphorylation. Therefore, FZR1 acts as sensor for P53-induced apoptosis in chemotherapy treatment and is correlated with prognosis and survival in patients with breast cancer59

 

The immunohistochemical detection of FZR1 supported its ability to be a predictor for neo-adjuvant chemotherapy efficacy in both animal and human samples. Collectively, FZR1 is a promising novel biomarker that could be used, on the clinical scale, for prediction of neo-adjuvant chemotherapy effect59.

 

Facio-genital dysplasia gene 3:

Facio-genital dysplasia gene 3 (FGD3) is located on the long arm of chromosome 9. It encodes for Rho guanine nucleotide exchange factor62. FGD3 gene was studied earlier by Hayakawa and coworkers, and was found to give transcription products with inhibitory effect on cell migration and proliferation63. Based on the evidence of another study, FGD3 was highly correlated with breast cancer survival rate and silencing of FGD3 blocked the expression of sushi domain containg 3 (SUSD3) as they located adjacent to each other on chromosome 9. FGD3–SUSD3 metagene was correlated with ER-positive breast cancer and was low expressed in ER-negative breast cancer. Moreover, the lack of FGD3-SUSD3 expression was correlated with bad prognosis64.

 

In 2017, FGD3 was confirmed to have prognostic value in cohort of breast cancer patients when compared with well-known markers of proliferation like proliferation cell nuclear antigen and marker of proliferation Ki-67. Moreover, FGD3 low expression was correlated with high degree of lymph node involvement and estradiol stimulation65.

 

FGD3 gene was studied to confirm its value as survival marker and a predictor of the outcome in patients within the same subgroup but with variable prognosis. By using immunohistochemical analysis, FGD3 gene was found as an independent marker of overall survival and its higher staining intensity was correlated with less lymph node involvement66,67,68. Thus, all in all, FGD3 gene could be used as an independent biomarker for breast cancer in the future as it can be detected by easy and cheap method like immunohistochemistry.

 

Serum biomarker:

Autotaxin –Lysophosphatidic acid:

Autotaxin (ATX) is an extracellular lysophospholipase D that can generate extracellular lypophosphatidic acid (LPA), which is a bioactive lipid that act through G protein coupled receptor to initiate cellular proliferation and survival69. Autotaxin is glycoprotein that was discovered as motility stimulating factor produced by human melanoma cells70. Increased ATX and LPA expression was documented in many cancer tissues including hepatocellular, thyroid and breast cancers71,72, 73.

 

In animal models, ATX–LPA pathway transduces breast epithelial inflammation and can lead to the development of invasive breast cancer73. Using breast cancer gene ChIP analysis, ATX was found to increase metastasis and high stromal expression of ATX is correlated with bone metastasis74,75,76. ATX acts through LPA which promote cell proliferation and invasion by stimulating synthesis of vascular endothelial growth factors and activating phosphatidyl inositol 3 kinase/extracellular signal regulated kinase (ERK) pathway. Furthermore, ATX can induce chemotherapy resistance and reverse paclitaxel-induced apoptosis and targeting it may increase chemotherapy and radiotherapy efficacy77,78,79.

 

Recent studies revealed the potential of serum ATX as a prognostic biomarker in breast cancer. Serum ATX level in breast cancer samples was significantly higher than its level in normal control in patients with grade 1, 2 and 3. Moreover, breast cancer patients with advanced TNM stage and high Ki-67 index showed higher level of serum ATX and the higher ATX level the worse the disease free survival rate is78,80. Collectively, serum ATX level can be used as a circulating prognostic biomarker for breast cancer cases.

 

Figure 2: Diagrammatic illustration of the conclusion

 

CONCLUSION:

In conclusion as illustrated in Figure 2; lipocalin 1, cysteine protease cathepsin and Ras 22a act as diagnostic biomarker. While heterogeneity nuclear proteins A2/B1, Autotaxin –Lysophosphatidic acid and Insulinoma associated protein 1 correlate with bad prognosis. On the other hand, Facio-genital dysplasia gene 3 and Fizzy-related protein 1 correlate with good outcomes. Future prospective clinical trials, in different centers and hospitals, are required to evaluate the exact implication of markers discussed in breast cancer cases.

 

CONFLICT OF INTEREST:

All authors claim that there is no conflict of interest in this review.

 

AUTHORS CONTRIBUTION:

Prof. Dr. Nahla El-Ashmawy: suggested the idea and reviewed the review for publication.

Prof Dr. Eman Khedr, Prof. Dr. Naglaa Khedr, Prof. Dr. Enas El-Zamarany: reviewed the article and approved it for publication.

Dr. Hend Selim: conducted the research, wrote the draft and approved for publication.

 

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Received on 13.12.2021           Modified on 27.02.2022

Accepted on 30.03.2022         © RJPT All right reserved

Research J. Pharm. and Tech. 2022; 15(8):3808-3813.

DOI: 10.52711/0974-360X.2022.00639