Modulation of the oncogene transcription factor TBX2 expression and autophagy in triple-negative breast Cancer cells

Abstract

Female Breast Cancer (BC) was the leading cause of global Cancer incidence in 2020, accounting for 11.7% of all cancer cases. In Brazil, there is a high prevalence, among young patients, of primary and metastatic tumors. Cancers classified as triple-negative (TNBCs) represent up to 24% of all BC cases, with no therapeutic options aimed at this tumor type. Defined by the absence of hormone receptors and her2 amplification, they are highly heterogeneous and aggressive than other BC subtypes. Studies have played a role for the transcription factor TBX2 in carcinogenesis, in which, in BC, it is known to drive its proliferation, being strongly implicated in tumor progression. One of the mechanisms by which the development of cancer can be controlled is autophagy, an active catabolic process, mediated by pathways that occur in all cells and activated by cellular stress, hypoxia and nutrient deprivation, being important for the maintenance of homeostasis in cellular and cellular stress responses. This process has tumor suppressor and promoter functions, which are presented at different stages of tumorigenesis. Previously, our research group identified the natural marine product chromomycin A5 (CA-5) as a molecule that has in vitro antitumor effects in melanoma cell lines through its direct action on TBX2. Studies with chromomycin A2 (CA-2) have shown that it induces autophagy and cell death in melanoma cells. However, to date we do not know if CA-5 is capable of inducing autophagy in TNBC cell lines. Thus, this project aims to investigate whether the pharmacological inhibition of TBX2 with CA-5 is able to induce autophagy in TNBC cell lines. We will use assays that verify the protein expression of autophagy markers; evaluation of acidification of intracellular compartments through AO labeling and immunofluorescence. We hope that these data provide us with clues about the pharmacodynamics of this natural compound of marine origin. (AU)