SOX7 is downregulated and functions as a tumor suppressive transcription factor in breast cancer.

摘要

Second only to lung cancer, breast cancer is the leading cause of cancer-related deaths in American women. Breast cancer is a heterogeneous set of diseases characterized by aberrant genetic and epigenetic states, often leading to the ablation of tumor suppressors. Loss of tumor suppressor function has been established as a driver of disease progression in breast cancer patients. Thus, understanding the deregulation of tumor suppressor activity may lead to the identification of potential therapeutic targets whose inhibition can restore tumor suppressor function and, consequently, an anti-proliferative cellular state.;The Sex-determining region Y-box (SOX) family of transcription factors plays important roles in development, and several of its members have also been heavily implicated in a variety of cancers. In particular, SOX7 downregulation and tumor suppressive activities have been reported in a variety of epithelial tumors, including those of the lung, colon, and prostate. However, the precise functions of SOX7 as a DNA-binding transcription factor remained understudied. We set out to interrogate the role of SOX7 in breast cancer and the mechanism behind its tumor-specific depletion. We report the frequent and striking downregulation of SOX7 in several breast cancer cell lines and breast tumor tissues, compared to normal mammary epithelia. The SOX7 promoter is frequently methylated in breast cancer cell lines, and SOX7 mRNA, but not protein, levels increase in response to pharmacologic or shRNA-mediated silencing of DNA methyltransferases (DNMTs). However, DNA methylation in breast tumor tissues is less common. Thus, we investigated the contribution of miRNAs to SOX7 downregulation and observed inhibition of a reporter plasmid with the SOX7 3' untranslated region (UTR) in response to cotransfection with miR-182. Further, we correlated reduced SOX7 expression in breast cancer cell lines and tumor tissues with levels of a noncoding RNA transcript, reverse-SOX7. Importantly, SOX7 expression correlates with better distant metastasis-free survival in breast cancer patients, indicating its clinical relevance as a potential prognostic marker for breast cancer. To assess the functional role of SOX7 in breast cancer, we generated constructs to silence SOX7 expression using shRNA and introduced Doxycycline-inducible ectopic SOX7. With these tools, we demonstrated the tumor suppressive role of SOX7 in breast cancer cells both in vitro and in vivo. We explored the transcriptional activities of SOX7 using a microarray, and identified several cancer-related pathways that are regulated by SOX7.;Collectively, our work demonstrates a critical role for SOX7 in antagonizing neoplastic transformation of mammary cells and explores multiple mechanisms by which breast tumors downregulate SOX7 expression.