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(American Journal of Pathology. 2005;167:409-417.)
© 2005 American Society for Investigative Pathology

Proliferation of Estrogen Receptor-{alpha}-Positive Mammary Epithelial Cells Is Restrained by Transforming Growth Factor-ß1 in Adult Mice

Kenneth B.R. Ewan, Hellen A. Oketch-Rabah, Shraddha A. Ravani, G. Shyamala, Harold L. Moses and Mary Helen Barcellos-Hoff

From the Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California

Transforming growth factor (TGF)-ß1 is a potent inhibitor of mammary epithelial proliferation. In human breast, estrogen receptor (ER)-{alpha} cells rarely co-localize with markers of proliferation, but their increased frequency correlates with breast cancer risk. To determine whether TGF-ß1 is necessary for the quiescence of ER-{alpha}-positive populations, we examined mouse mammary epithelial glands at estrus. Approximately 35% of epithelial cells showed TGF-ß1 activation, which co-localized with nuclear receptor-phosphorylated Smad 2/3, indicating that TGF-ß signaling is autocrine. Nuclear Smad co-localized with nuclear ER-{alpha}. To test whether TGF-ß inhibits proliferation, we examined genetically engineered mice with different levels of TGF-ß1. ER-{alpha} co-localization with markers of proliferation (ie, Ki-67 or bromodeoxyuridine) at estrus was significantly increased in the mammary glands of Tgfß1 C57/bl/129SV heterozygote mice. This relationship was maintained after pregnancy but was absent at puberty. Conversely, mammary epithelial expression of constitutively active TGF-ß1 via the MMTV promoter suppressed proliferation of ER-{alpha}-positive cells. Thus, TGF-ß1 activation functionally restrains ER-{alpha}-positive cells from proliferating in adult mammary gland. Accordingly, we propose that TGF-ß1 dysregulation may promote proliferation of ER-{alpha}-positive cells associated with breast cancer risk in humans.




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