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PMID: 16049327 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Proliferation of estrogen receptor-alpha-positive mammary epithelial cells is restrained by transforming growth factor-beta1 in adult mice.

The American journal of pathology ·Vol. 167 ·No. 2 ·2005-08-00 ·Pages 409-17

Ewan KB, Oketch-Rabah HA, Ravani SA, Shyamala G, Moses HL, Barcellos-Hoff MH

Abstract

Transforming growth factor (TGF)-beta1 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-beta1 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-beta1 activation, which co-localized with nuclear receptor-phosphorylated Smad 2/3, indicating that TGF-beta signaling is autocrine. Nuclear Smad co-localized with nuclear ER-alpha. To test whether TGF-beta inhibits proliferation, we examined genetically engineered mice with different levels of TGF-beta1. ER-alpha co-localization with markers of proliferation (ie, Ki-67 or bromodeoxyuridine) at estrus was significantly increased in the mammary glands of Tgf beta1 C57/bl/129SV heterozygote mice. This relationship was maintained after pregnancy but was absent at puberty. Conversely, mammary epithelial expression of constitutively active TGF-beta1 via the MMTV promoter suppressed proliferation of ER-alpha-positive cells. Thus, TGF-beta1 activation functionally restrains ER-alpha-positive cells from proliferating in adult mammary gland. Accordingly, we propose that TGF-beta1 dysregulation may promote proliferation of ER-alpha-positive cells associated with breast cancer risk in humans.

Keywords
Non-programmatic
MeSH Terms
Animals Cell Proliferation Crosses, Genetic DNA-Binding Proteins/metabolism Epithelial Cells/metabolism,pathology Estrogen Receptor alpha/metabolism Estrus/metabolism Female Heterozygote Mammary Glands, Animal/metabolism,pathology Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Phosphorylation Smad2 Protein Trans-Activators/metabolism Transforming Growth Factor beta/genetics,physiology Transforming Growth Factor beta1
Chemicals
DNA-Binding Proteins Estrogen Receptor alpha Smad2 Protein Smad2 protein, mouse TGFB1 protein, human Tgfb1 protein, mouse Trans-Activators Transforming Growth Factor beta Transforming Growth Factor beta1
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Ewan Kenneth B R
Life Sciences Division, Bldg. 74-355, 1 Cyclotron Rd., Lawrence Berkeley National Laboratory, Berkeley CA 94720, USA.
Oketch-Rabah Hellen A
Ravani Shraddha A
Shyamala G
Moses Harold L
Barcellos-Hoff Mary Helen
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.1016/s0002-9440(10)62985-9
Published
2005-08-00
Pages
409-17
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1603552
Subset
IM
Grants
NIA NIH HHS · R01 AG022413 · United States
External Links
PubMed source DOI: 10.1016/s0002-9440(10)62985-9 PMC Full Text View journal details
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