EXAMINING MECHANISTIC UNDERPINNINGS OF CHEMORESISTANCE IN TRIPLE NEGATIVE BREAST CANCER

Abstract

Background: Triple negative breast cancer (TNBC) is not only the most aggressive subtype of breast cancer, but it does also not have many targeted therapeutic options due to the lack of hormone receptor expression and enrichment of HER2. TNBCs are also more prone to the development of chemoresistance and metastatic progression, which are the main obstacles to reducing TNBC-related mortality. Question: The objective of this study is to identify targetable key node (s) that contribute to the development of chemoresistance in TNBC. Method: Differentially expressed genes in TNBC patients with or without relapse were analyzed to select functionally important genes in chemoresistant TNBC. TRIM29 was selected based on survival analysis. Carboplatin-resistant TNBC cells were established to explore the phenotypic and molecular differences. Various growth and migration assays were used to explore the phenotype of chemoresistant TNBC cells. Expression of TRIM29 and related pathways were assessed by immunoblotting and immunofluorescence analysis. Cells with TRIM29-knockout (KO) were established by the CRISPR system. Result: Chemoresistant TNBC cells overexpress TRIM29. Exhibiting the functional importance, overexpression of TRIM29 in MDAMB231 confers resistance to carboplatin. A stable knockout of TRIM29 in carboplatin-resistant cells results in improved response to carboplatin. Mechanistically, an enhanced expression of β-catenin and YAP1 is observed in chemoresistant as well as TRIM29-overxpressing cells. Both β-catenin and YAP1 exhibit nuclear colocalization in TRIM29-overexpressing cells. TRIM29-KO in carboplatin-resistant HCC1806 results in a drastic decrease in β-catenin level, but, paradoxically an increased level of YAP1 is observed indicating a feedback loop demanding further investigation. Conclusion:Our findings implicate TRIM29 enrichment as an important node in chemoresistant TNBC that may concomitantly modulate YAP1 and β-catenin as downstream oncogenic effectors.