PMID- 23705924 OWN - NLM STAT- MEDLINE DCOM- 20150312 LR - 20211021 IS - 1465-542X (Electronic) IS - 1465-5411 (Print) IS - 1465-5411 (Linking) VI - 15 IP - 3 DP - 2013 May 25 TI - Amphiregulin mediates progesterone-induced mammary ductal development during puberty. PG - R44 LID - 10.1186/bcr3431 [doi] AB - INTRODUCTION: Puberty is a period of increased susceptibility to factors that cause increased breast cancer risk in adulthood. Mammary end buds (EBs) that develop during puberty are believed to be the targets of breast cancer initiation. Whereas the role of estrogen (E) has been extensively studied in pubertal mammary gland development, the role of progesterone (P) during puberty is less defined. METHODS: Pubertal and prepubertal ovariectomized mice were treated with vehicle control (C), E, P, or E+P. Mammary glands from these mice were analyzed for changes in morphology, proliferation, and expression of the downstream targets amphiregulin (AREG) and receptor activator of NF-kappaB ligand (RANKL). RESULTS: P, acting specifically through the progesterone receptor, induced increases in mammary gland proliferation and EB formation that were associated with increased AREG expression in ducts and EBs. E, acting specifically through the estrogen receptor, produced similar responses also mediated by AREG. Blocking AREG action by treatment with an EGFR inhibitor completely abrogated the effect of P on EB formation and proliferation and significantly reduced proliferation within ducts. P also increased expression of RANKL, primarily in ducts. Treatment with RANK-Fc, an inhibitor of RANKL, reduced P-dependent proliferation in ducts and to a lesser extent in EB, but did not cause EB regression. CONCLUSIONS: These results demonstrate a novel P-specific effect through AREG to cause EB formation and proliferation in the developing mammary gland both before and during puberty. Thus, hormones and/or factors in addition to E that upregulate AREG can promote mammary gland development and have the potential to affect breast cancer risk associated with pubertal mammary gland development. FAU - Aupperlee, Mark D AU - Aupperlee MD FAU - Leipprandt, Jeffrey R AU - Leipprandt JR FAU - Bennett, Jessica M AU - Bennett JM FAU - Schwartz, Richard C AU - Schwartz RC FAU - Haslam, Sandra Z AU - Haslam SZ LA - eng GR - U01 ES019434/ES/NIEHS NIH HHS/United States GR - 1 U01 ESO1943/PHS HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20130525 PL - England TA - Breast Cancer Res JT - Breast cancer research : BCR JID - 100927353 RN - 0 (Amphiregulin) RN - 0 (Estrogens) RN - 0 (RANK Ligand) RN - 0 (Tnfsf11 protein, mouse) RN - 4G7DS2Q64Y (Progesterone) SB - IM MH - Amphiregulin/*biosynthesis/metabolism MH - Animals MH - Cell Proliferation/drug effects MH - Estrogens/administration & dosage/*metabolism MH - Female MH - Gene Expression Regulation, Neoplastic/drug effects MH - Humans MH - Mammary Glands, Animal/drug effects/*growth & development MH - Mice MH - Ovariectomy MH - Progesterone/administration & dosage/*metabolism MH - Puberty/drug effects/metabolism MH - RANK Ligand/biosynthesis MH - Risk Factors PMC - PMC3738150 EDAT- 2013/05/28 06:00 MHDA- 2015/03/13 06:00 PMCR- 2013/05/25 CRDT- 2013/05/28 06:00 PHST- 2012/10/30 00:00 [received] PHST- 2013/05/25 00:00 [accepted] PHST- 2013/05/28 06:00 [entrez] PHST- 2013/05/28 06:00 [pubmed] PHST- 2015/03/13 06:00 [medline] PHST- 2013/05/25 00:00 [pmc-release] AID - bcr3431 [pii] AID - 10.1186/bcr3431 [doi] PST - epublish SO - Breast Cancer Res. 2013 May 25;15(3):R44. doi: 10.1186/bcr3431.