TY - JOUR
T1 - Transforming growth factor-β can suppress tumorigenesis through effects on the putative cancer stem or early progenitor cell and committed progeny in a breast cancer xenograft model
AU - Tang, Binwu
AU - Yoo, Naomi
AU - Vu, Mary
AU - Mamura, Mizuko
AU - Nam, Jeong Seok
AU - Ooshima, Akira
AU - Du, Zhijun
AU - Desprez, Pierre Yves
AU - Anver, Miriam R.
AU - Michalowska, Aleksandra M.
AU - Shih, Joanna
AU - Parks, W. Tony
AU - Wakefield, Lalage M.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2007/9/15
Y1 - 2007/9/15
N2 - The transforming growth factor-β (TGF-β) pathway has tumor-suppressor activity in many epithelial tissues. Because TGF-β 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-β 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-β 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-β 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-β involves down-regulation of Id1, and forced overexpression of Id1 can promote tumorigenesis despite persistence of the antiproliferative effect of TGF-β. These data suggest new roles for the TGF-β pathway in regulating tumor cell dynamics that are independent of direct effects on proliferation.
AB - The transforming growth factor-β (TGF-β) pathway has tumor-suppressor activity in many epithelial tissues. Because TGF-β 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-β 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-β 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-β 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-β involves down-regulation of Id1, and forced overexpression of Id1 can promote tumorigenesis despite persistence of the antiproliferative effect of TGF-β. These data suggest new roles for the TGF-β pathway in regulating tumor cell dynamics that are independent of direct effects on proliferation.
UR - http://www.scopus.com/inward/record.url?scp=34548706039&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34548706039&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-07-0982
DO - 10.1158/0008-5472.CAN-07-0982
M3 - Article
C2 - 17875704
AN - SCOPUS:34548706039
VL - 67
SP - 8643
EP - 8652
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 18
ER -