Transcription factor activator protein 2C and downstream redox biology effectors in development and carcinogenesis

Breast cancer is a heterogeneous disease with multiple phenotypes that specify both treatment options and prognosis. The Luminal A-type breast cancers, characterized by high levels of estrogen receptor (ER) expression and transcriptional activity, have a stable of hormone-related treatment options and a favorable prognosis. Recent efforts to identify mechanisms governing the Luminal A phenotype have identified transcription factor activator protein 2C (TFAP2C) as a critical regulator of both ER and ER-associated gene expression, making it a prime target for manipulation in breast cancer therapy. To that end, we sought to establish specific contributions of TFAP2C in both normal development and cancer progression, with the overarching hypothesis that TFAP2C is an integral transcription factor in maintaining a luminal differentiation and expression pattern in human breast cancer. To address this, we utilized several parallel approaches to identify potential TFAP2C-related contributions to carcinogenesis. In the first approach, we identified that tissue-specific abrogation of the mouse homolog TCFAP2C in mammary epithelium produced a reduction in luminal populations and a concomitant increase in basal populations, producing mild phenotypic alterations in gland structure. In the second, we stably manipulated TFAP2C expression in the established Luminal A model cell line MCF-7, establishing that TFAP2C loss promotes a loss of luminal differentiation characteristics and a gain of basal / mesenchymal traits, mirroring the results found in the mouse model. As a final approach, we examined the role of a TFAP2C target gene, manganese superoxide dismutase (MnSOD), in modulating redox biological and epigenetic parameters that may contribute to carcinogenesis. We found that loss of MnSOD in the murine liver, chosen because of its utility as a model system, promoted subtle changes in the redox buffering capacity and identified preliminary changes in the epigenome, suggesting that MnSOD modulation by TFAP2C could play a role in cancer development. Overall, these results further establish a role of TFAP2C in the genesis of Luminal A breast cancer, and serve as a foundation for more comprehensive future work evaluating specific contributions in carcinogenesis.