Abstract 1720: Examining mechanistic underpinnings of chemoresistance in triple negative breast cancer

Abstract

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. 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. The expression of TRIM29 and related pathways were assessed by immunoblotting and immunofluorescence analysis. Cells with TRIM29-knockout (KO) were developed 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 an improved response to carboplatin. The breast tumor xenograft model revealed that TRIM29-KO in chemoresistant TNBC formed significantly less dense tumor in mice compared to control. Mechanistically, an enhanced expression of β-catenin was seen in chemoresistant as well as TRIM29-overexpressing cells. TRIM29-KO in carboplatin-resistant cell line results in a drastic decrease in β-catenin level. Combination treatment of carboplatin and β-catenin-inhibitor resulted in an enhanced growth inhibition in chemoresistant TNBC cells. RNA-Seq analysis revealed that there are 24 candidate genes which are overexpressed in chemoresistant TNBC cells but downregulated in TRIM29-KO chemoresistant cells, thereby demanding further investigation. Conclusion: Our findings implicate TRIM29 enrichment as an important node in chemoresistant TNBC that may concomitantly modulate β-catenin as downstream oncogenic effectors. Citation Format: Qitong Wu, Sumit Siddharth, Deepak Verma, Sheetal Parida, Dipali Sharma. Examining mechanistic underpinnings of chemoresistance in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1720.