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

Baylor College of Medicine, Houston, Texas, United States
Cancer Research (Impact Factor: 9.33). 10/2007; 67(18):8643-52. DOI: 10.1158/0008-5472.CAN-07-0982
Source: PubMed


The transforming growth factor-beta (TGF-beta) pathway has tumor-suppressor activity in many epithelial tissues. Because TGF-beta 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-beta 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-beta 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-beta 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-beta involves down-regulation of Id1, and forced overexpression of Id1 can promote tumorigenesis despite persistence of the antiproliferative effect of TGF-beta. These data suggest new roles for the TGF-beta pathway in regulating tumor cell dynamics that are independent of direct effects on proliferation.

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Available from: Lalage M Wakefield
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    • "The PCSLCs were cultured with DMEM/F12 (1:1) supplemented with 5 μg/l TGF-β (Peprotech, Inc.) and 1% fetal calf serum (14). The PCSLCs that were cultured without TGF-β were used as a control group. "
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    • "For example, TGF-β signaling is pivotal in the maintenance of cancer stem cell self-renewal and tumorigenic activity in glioma and leukaemia, whereas the effects of TGF-β signaling in breast cancer stem cell are controversial [12]. One study showed that blocking TGF-β pathway via a dominant negative TGF-βRII increases the size of breast stem cell compartment and promotes tumorigenesis, indicating a suppression of breast carcinogenesis of this cytokine [13]. By contrast, Mani and colleagues found that TGF-β pathway us critical in the maintenance of breast cancer stem cell-like properties and tumorigenic activity via inducing EMT [14]. "
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