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

ABSTRACT: ERα is one of the most important transcription factors and therapeutic targets in breast cancer. The patterns of ERα expression in normal breast tissue and cancerous lesions are strikingly different. What drives the change of ERα 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 ERα 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 ERα+ 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 ERα+ luminal cells. Mechanistic study identifies Ccnd1 as a novel target of miR-200c/141 . Upon miR-200c/141deletion, elevated Ccnd1 level corroborates ERα transcriptional activation, leads to enhanced ERα signaling activity, consequently increased transcription of ERα coding gene Esr1 through self-activation at promoter E1. Our findings reveal a new miR-200c/141-Ccnd1-ERα 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 ERα expression pattern.

ORGANISM(S): Mus musculus

PROVIDER: GSE173815 | GEO | 2021/05/05

REPOSITORIES: GEO

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MicroRNA-200c/141 confines ERα activity and expression pattern by targeting Ccnd1 [single-cell RNA-seq]

Project description:ERα is one of the most important transcription factors and therapeutic targets in breast cancer. The patterns of ERα expression in normal breast tissue and cancerous lesions are strikingly different. What drives the change of ERα 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 ERα 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 ERα+ 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 ERα+ luminal cells. Mechanistic study identifies Ccnd1 as a novel target of miR-200c/141 . Upon miR-200c/141deletion, elevated Ccnd1 level corroborates ERα transcriptional activation, leads to enhanced ERα signaling activity, consequently increased transcription of ERα coding gene Esr1 through self-activation at promoter E1. Our findings reveal a new miR-200c/141-Ccnd1-ERα 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 ERα expression pattern.

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