Growth Factors, Cytokines, Cell Cycle Molecules Proliferation of Estrogen Receptor- -Positive Mammary Epithelial Cells Is Restrained by Transforming Growth Factor- 1 in Adult Mice

Transforming growth factor (TGF)1 is a potent inhibitor of mammary epithelial proliferation. In human breast, estrogen receptor (ER)cells rarely colocalize with markers of proliferation, but their increased frequency correlates with breast cancer risk. To determine whether TGF1 is necessary for the quiescence of ER-positive populations, we examined mouse mammary epithelial glands at estrus. Approximately 35% of epithelial cells showed TGF1 activation, which co-localized with nuclear receptorphosphorylated Smad 2/3, indicating that TGFsignaling is autocrine. Nuclear Smad co-localized with nuclear ER. To test whether TGFinhibits proliferation, we examined genetically engineered mice with different levels of TGF1. ERco-localization with markers of proliferation (ie, Ki-67 or bromodeoxyuridine) at estrus was significantly increased in the mammary glands of Tgf 1 C57/bl/129SV heterozygote mice. This relationship was maintained after pregnancy but was absent at puberty. Conversely, mammary epithelial expression of constitutively active TGF1 via the MMTV promoter suppressed proliferation of ER-positive cells. Thus, TGF1 activation functionally restrains ER-positive cells from proliferating in adult mammary gland. Accordingly, we propose that TGF1 dysregulation may promote proliferation of ER-positive cells associated with breast cancer risk in humans. (Am J Pathol 2005, 167:409–417)

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