BRCA1 Interactors - Rad50 and BRIP1: As Prognostic and Predictive Molecules for the Severity of Triple-Negative Breast Cancer

Author(s):  
Suparna Laha ◽  
Muhseena N Katheeja ◽  
Shankar Das ◽  
Ranajit Das

Abstract BRIP1 is one of the major interacting partner of BRCA1 which plays an important role in repair by homologous recombination (HR). This gene is mutated in around 4% cases of breast cancer, however, its mechanism of action is unclear. In this study, we presented the fundamental role of BRCA1 interactors BRIP1 and RAD50 in the development of differential severity in Triple-Negative Breast Cancer(TNBC) among various affected individuals. We showed that in some TNBC lines like MDA-MB-231 the functioning of both BRCA1/TP53 is compromised. Furthermore, the sensing of DNA damage is affected, depicted through the low expression of damage sensing molecule Rad50 and reduced formation of H2AX foci. Due to less damage sensing capability and low availability of BRCA1 at the damage sites, the repair by HR becomes inefficient leading to more damage. Accumulation of damage sends a signal for over activation of NHEJ repair pathways. Over expressed NHEJ molecules with compromised HR and checkpoint conditions lead to higher proliferation and error-prone repair, which increases the mutation rate and corresponding tumor severity. The severity phenotypes were more in cells having compromised BRCA1-BRIP1 functioning. The in silico analysis of the TCGA-UCSC xena datasets with genes expression in deceased population shows a significant correlation of BRCA1 expression with OS in TNBCs (0.0272). The association of BRCA1 with OS becomes stronger with the addition of BRIP1expression (0.000876**). Since the overall survival(OS) is directly proportional to the extent of severity, the data analysis hints at the role of BRIP1 in controlling the severity of TNBC.

Oncotarget ◽  
2016 ◽  
Vol 7 (15) ◽  
pp. 20068-20079 ◽  
Author(s):  
Nerea Matamala ◽  
Maria Teresa Vargas ◽  
Ricardo González-Cámpora ◽  
Jose Ignacio Arias ◽  
Primitiva Menéndez ◽  
...  

2021 ◽  
Vol 32 ◽  
pp. S28
Author(s):  
A. Bosch ◽  
M. Cieśla ◽  
P. Cao Thi Ngoc ◽  
S. Mutukumar ◽  
G. Honeth ◽  
...  

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 462
Author(s):  
Víctor Mayoral-Varo ◽  
María Pilar Sánchez-Bailón ◽  
Annarica Calcabrini ◽  
Marta García-Hernández ◽  
Valerio Frezza ◽  
...  

The role of Src family kinases (SFKs) in human tumors has been always associated with tyrosine kinase activity and much less attention has been given to the SH2 and SH3 adapter domains. Here, we studied the role of the c-Src-SH2 domain in triple-negative breast cancer (TNBC). To this end, SUM159PT and MDA-MB-231 human cell lines were employed as model systems. These cells conditionally expressed, under tetracycline control (Tet-On system), a c-Src variant with point-inactivating mutation of the SH2 adapter domain (R175L). The expression of this mutant reduced the self-renewal capability of the enriched population of breast cancer stem cells (BCSCs), demonstrating the importance of the SH2 adapter domain of c-Src in the mammary gland carcinogenesis. In addition, the analysis of anchorage-independent growth, proliferation, migration, and invasiveness, all processes associated with tumorigenesis, showed that the SH2 domain of c-Src plays a very relevant role in their regulation. Furthermore, the transfection of two different aptamers directed to SH2-c-Src in both SUM159PT and MDA-MB-231 cells induced inhibition of their proliferation, migration, and invasiveness, strengthening the hypothesis that this domain is highly involved in TNBC tumorigenesis. Therefore, the SH2 domain of c-Src could be a promising therapeutic target and combined treatments with inhibitors of c-Src kinase enzymatic activity may represent a new therapeutic strategy for patients with TNBC, whose prognosis is currently very negative.


2016 ◽  
Vol 38 (3) ◽  
pp. 1003-1014 ◽  
Author(s):  
Aiyu Zhu ◽  
Yan Li ◽  
Wei Song ◽  
Yumei Xu ◽  
Fang Yang ◽  
...  

Background/Aims: Androgen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells. Methods: MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide. Results: We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively. Conclusions: Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients.


Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3357
Author(s):  
Hongmei Zheng ◽  
Sumit Siddharth ◽  
Sheetal Parida ◽  
Xinhong Wu ◽  
Dipali Sharma

Triple negative breast cancer (TNBC) is a heterogeneous disease and is highly related to immunomodulation. As we know, the most effective approach to treat TNBC so far is still chemotherapy. Chemotherapy can induce immunogenic cell death, release of damage-associated molecular patterns (DAMPs), and tumor microenvironment (TME) remodeling; therefore, it will be interesting to investigate the relationship between chemotherapy-induced TME changes and TNBC immunomodulation. In this review, we focus on the immunosuppressive and immunoreactive role of TME in TNBC immunomodulation and the contribution of TME constituents to TNBC subtype classification. Further, we also discuss the role of chemotherapy-induced TME remodeling in modulating TNBC immune response and tumor progression with emphasis on DAMPs-associated molecules including high mobility group box1 (HMGB1), exosomes, and sphingosine-1-phosphate receptor 1 (S1PR1), which may provide us with new clues to explore effective combined treatment options for TNBC.


2021 ◽  
Author(s):  
Ximena Minerva Bustamante-Marin ◽  
Kaylyn L. Devlin ◽  
Om Dave ◽  
Jenna L. Merlino ◽  
Shannon B. McDonell ◽  
...  

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