MicroRNA-200c/141 confines ERa activity and expression pattern by targeting Ccnd1 [bulk RNA-seq]

ERa is one of the most important transcription factors and therapeutic targets in breast cancer. The patterns of ERa expression in normal breast tissue and cancerous lesions are strikingly different. What drives the change of ERa pattern during lesions formation remains unclear. Here, we describe a novel regulatory mechanism through which miR-200c/141 regulates the level as well as the distribution of ERa in the mammary gland. miR-200c/141 is specifically expressed in luminal cells. Luminal-deletion of miR-200c/141 (miR-cKO) leads to a drastic expansion of ERa+ cell proportion. Single cell RNAseq reveals that miR-cKO generates aberrant luminal subpopulations with increased proliferative and anti-apoptotic features. In vivo lineage tracing of ER- luminal cells demonstrates that miR-200c/141 deletion can convert ER- cells into ER+ cells, which contribute partly to the increase of ERa+ luminal cells. Mechanistic study identifies Ccnd1 as a novel target of miR-200c/141 . Upon miR-200c/141deletion, elevated Ccnd1 level corroborates ERa transcriptional activation, leads to enhanced ERa signaling activity, consequently increased transcription of ERa coding gene Esr1 through self-activation at promoter E1. Our findings reveal a new miR-200c/141-Ccnd1-ERa axis, and provide new molecular insights into how miR-200c/141-Ccnd1 enforces the lineage barrier between ER- and ER+ luminal cells, and what drives the change of ERa expression pattern. Overall design: Examination of gene expression changes in mouse mammary luminal cells after knockout of miR-200c/141.