title: Research resource: progesterone receptor targetome underlying mammary gland branching morphogenesis.
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.
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. orlac@bcm.edu.
authors: Ashlee R
authors: AR
authors: Lain
authors: Chad J
authors: CJ
authors: Creighton
authors: Orla M
authors: OM
authors: Conneely
mesh_terms: D000818:Animals; D004848:Epithelium / Q000378:metabolism; D004958:Estradiol / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis; D011374:Progesterone / Q000502:physiology*; D011980:Receptors, Progesterone / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D011980:Receptors, Progesterone; D011374:Progesterone; D004958:Estradiol; D020744:rac GTP-Binding Proteins
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