Research resource: progesterone receptor targetome underlying mammary gland branching morphogenesis.
Mol Endocrinol, 2013/10;27(10):1743-61.
Lain AR[1], Creighton CJ, Conneely OM
Affiliations
PMID: 23979845DOI: 10.1210/me.2013-1144
Abstract
Progesterone (P4)-activated progesterone receptors (PRs) play an essential role in driving pregnancy-associated mammary ductal side-branching morphogenesis and alveologenesis. However, the global cistromic and transcriptome responses that are required to elicit P4-dependent branching morphogenesis have not been elucidated. By combining chromatin immunoprecipitation followed by deep sequencing to identify genome-wide PR-binding sites in PR-positive luminal epithelial cells with global gene expression signatures acutely regulated by PRs in the mammary gland, we have identified a mammary epithelial PR targetome associated with active P4-dependent branching morphogenesis in vivo. We demonstrate that P4-induced side-branching is initiated by epithelial cell rearrangement into a multilayered epithelium that sprouts laterally from quiescent ducts via a mechanism requiring P4-dependent activation of Rac-GTPase signaling. We identify effectors of Rac-GTPases as direct transcriptional targets of PRs, and we demonstrate that disruption of the P4-activated Rac-GTPase signaling axis is sufficient to eliminate P4-dependent side-branching. Our data reveal that the molecular mediators of P4-dependent ductal side-branching overlap with those implicated in breast cancer.
MeSH terms
Animals; Epithelium; Estradiol; Female; Gene Expression Regulation; Mammary Glands, Animal; Mice, 129 Strain; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Morphogenesis; Progesterone; Receptors, Progesterone; Signal Transduction; Transcriptome; rac GTP-Binding Proteins
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