Abstract 2891: Retinoic acid directs breast cancer cell state changes through regulation of TET2-aPKC pathway

The key molecular mechanism governing the cancer cell state (stem cell-like state vs. differentiation state) to control the cancer stem cell (CSC) pool remains elusive. This study provides the first evidence showing that all-trans retinoic acid (ATRA) induces the interaction and chromatin recruitment of a novel RARB-TET2 complex to epigenetically activate a specific cohort of gene targets, including MiR-200c. TET2-activated miR-200c further targets and suppresses aPKC, a cell polarity protein that plays a pivotal role in directing asymmetric division of mammalian stem cells to sustain the stem cell pool. Our data reveals that pharmacological concentration of ATRA effectively down-regulates aPKC through activation of miR-200c, leading to a decrease of the stem cell-like populations from non-tumorigenic mammary epithelial cells and non-aggressive breast cancer cells. However, aggressive breast cancer cells that manifest TET2-miR200c dysregulation sustain a CSC pool highly resistant to ATRA, where inhibition of aPKC directs the resistant CSCs to the luminal cell-like state and sensitization to Tamoxifen, resulting in abrogation of mammary tumor growth and progression. Together, these findings elucidate a novel RARB-TET2-miR200c-aPKC signaling pathway that directs cancer cell state changes and also provide previously unidentified therapeutic implications for aPKC inhibitors in diminishment of breast CSCs to eradicate breast cancer. Citation Format: Meng-Ju Wu, Chun-Ju Chang. Retinoic acid directs breast cancer cell state changes through regulation of TET2-aPKC pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2891. doi:10.1158/1538-7445.AM2017-2891