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Open Access Research article

Amphiregulin mediates progesterone-induced mammary ductal development during puberty

Mark D Aupperlee1*, Jeffrey R Leipprandt1, Jessica M Bennett1, Richard C Schwartz2 and Sandra Z Haslam1

Author Affiliations

1 Department of Physiology, Michigan State University, 567 Wilson Rd., East Lansing, MI 48824, USA

2 Department of Microbiology and Molecular Genetics, Michigan State University, 567 Wilson Rd., East Lansing, MI 48824, USA

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Breast Cancer Research 2013, 15:R44  doi:10.1186/bcr3431

Published: 25 May 2013

Abstract

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-κB 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.