Journal Article

Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland

Ayyanan, Ayyakkannu, Germano, Davide, Rajaram, Renuga Devi, Brisken, Cathrin, Schneider, Pascal, Caikovski, Marian, Beleut, Manfred, Choi, Yongwon

2010

Overview

The mouse mammary gland develops postnatally under the control of female reproductive hormones. Estrogens and progesterone trigger morphogenesis by poorly understood mechanisms acting on a subset of mammary epithelial cells (MECs) that express their cognate receptors, estrogen receptor α (ERα) and progesterone receptor (PR). Here, we show that in the adult female, progesterone drives proliferation of MECs in two waves. The first, small wave, encompasses PR(+) cells and requires cyclin D1, the second, large wave, comprises mostly PR(-) cells and relies on the tumor necrosis factor (TNF) family member, receptor activator of NF-κB-ligand (RANKL). RANKL elicits proliferation by a paracrine mechanism. Ablation of RANKL in the mammary epithelium blocks progesterone-induced morphogenesis, and ectopic expression of RANKL in MECs completely rescues the PR⁻/⁻ phenotype. Systemic administration of RANKL triggers proliferation in the absence of PR signaling, and injection of a RANK signaling inhibitor interferes with progesterone-induced proliferation. Thus, progesterone elicits proliferation by a cell-intrinsic and a, more important, paracrine mechanism.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: adults / Animals / Beta cells / Biological Sciences / Breast cancer / Bromodeoxyuridine / Cell growth / Cell Proliferation - drug effects / Cells / Cyclin D1 - metabolism / Cyclin D1 - pharmacology / Cyclins / Epithelial cells / Epithelial Cells - metabolism / Epithelial Cells - physiology / Epithelium / estrogen receptors / Estrogens / Exocrine glands / Female / Females / Hormones / Immunohistochemistry / Mammary glands / Mammary Glands, Animal - cytology / Mammary Glands, Animal - growth & development / Mice / Mice, Knockout / morphogenesis / phenotype / Progesterone / Progesterone - metabolism / Progesterone - pharmacology / Progesterone receptors / RANK Ligand - genetics / RANK Ligand - metabolism / RANK Ligand - pharmacology / Receptors / Rodents / tumor necrosis factors