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Transforming Growth Factor-ß Can Suppress Tumorigenesis through Effects on the Putative Cancer Stem or Early Progenitor Cell and Committed Progeny in a Breast Cancer Xenograft Model

¹ Laboratory of Cell Regulation and Carcinogenesis and ² Biometric Research Branch, National Cancer Institute, Bethesda, Maryland; ³ Baylor College of Medicine, Houston, Texas; ⁴ California Pacific Medical Center, San Francisco, California; ⁵ Pathology/Histotechnology Laboratory, National Cancer Institute at Frederick, Frederick, Maryland; and ⁶ Department of Pathology, University of Washington, Seattle, Washington

Requests for reprints: Lalage Wakefield, National Cancer Institute, Building 37, Room 4032A, 37 Convent Drive MSC 4255, Bethesda, MD 20892-4255. Phone: 301-496-8351; Fax: 301-496-8709; E-mail: lw34g{at}nih.gov.

The transforming growth factor-ß (TGF-ß) pathway has tumor-suppressor activity in many epithelial tissues. Because TGF-ß is a potent inhibitor of epithelial cell proliferation, it has been widely assumed that this property underlies the tumor-suppressor effect. Here, we have used a xenograft model of breast cancer to show that endogenous TGF-ß has the potential to suppress tumorigenesis through a novel mechanism, involving effects at two distinct levels in the hierarchy of cellular progeny that make up the epithelial component of the tumor. First, TGF-ß reduces the size of the putative cancer stem or early progenitor cell population, and second it promotes differentiation of a more committed, but highly proliferative, progenitor cell population to an intrinsically less proliferative state. We further show that reduced expression of the type II TGF-ß receptor correlates with loss of luminal differentiation in a clinical breast cancer cohort, suggesting that this mechanism may be clinically relevant. At a molecular level, the induction of differentiation by TGF-ß involves down-regulation of Id1, and forced overexpression of Id1 can promote tumorigenesis despite persistence of the antiproliferative effect of TGF-ß. These data suggest new roles for the TGF-ß pathway in regulating tumor cell dynamics that are independent of direct effects on proliferation. [Cancer Res 2007;67(18):8643–52]

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