Retinoic acid directs breast cancer cell state changes through regulation of TET2-PKC? pathway.

ABSTRACT: 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 RAR?-TET2 complex to epigenetically activate a specific cohort of gene targets, including MiR-200c. TET2-activated miR-200c further targets and suppresses PKC?, a cell polarity protein that has a pivotal role in directing asymmetric division of mammalian stem cells to sustain the stem cell pool. Our data reveal that pharmacological concentration of ATRA effectively downregulates PKC? 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-miR-200c dysregulation sustain a CSC pool highly resistant to ATRA, where inhibition of PKC? 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 RAR?-TET2-miR-200c-PKC? signaling pathway that directs cancer cell state changes and also provide previously unidentified therapeutic implications for PKC? inhibitors in diminishment of breast CSCs to eradicate breast cancer.

SUBMITTER: Wu MJ 

PROVIDER: S-EPMC5541263 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature