Activated type I TGFbeta receptor (Alk5) kinase confers enhancedsurvival to mammary epithelial cells and accelerates mammary tumorprogression Page: 4 of 33
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al., 1999; Liu et al., 1997), the role of non-Smad effectors on mediating the cellular effects of TGFP is
less well characterized.
TGFP can behave as both a tumor suppressor and a tumor promoter. Its tumor suppressor role can be
explained by its ability to inhibit mitogenesis (Alexandrow and Moses, 1995), induce apoptosis (Siegel
and Massague, 2003), maintain tissue architecture (Engle et al., 1999), inhibit genomic instability (Glick
et al., 1996), and induce replicative senescence (Boulanger et al., 2004; Kordon et al., 1995). Consistent
with its anti-proliferative effect, overexpression of active TGF31 or TPRI in the mammary gland of
transgenic mice delays gland ductal extension and alveolar development (Jhappan et al., 1993; Pierce et
al., 1993; Siegel et al., 2003) and protects from oncogene- or carcinogen-induced transformation (Pierce
et al., 1995). In addition, attenuation of autocrine growth control by expression of dominant-negative
TPRII in the mouse mammary gland results in enhanced propensity for carcinogen-induced and
spontaneous mammary cancers (Bottinger et al., 1997; Gorska et al., 2003). Overexpression of TGF03
in alveolar epithelium of lactating mice causes alveolar cell apoptosis whereas Smad3-null mammary
epithelium exhibits impaired post-lactational involution and cell death (Nguyen and Pollard, 2000; Yang
et al., 2002), further consistent with the tumor suppressive role of TGFP. However, other data suggest
that TGFP can also act as a survival factor in normal mammary epithelium. During pregnancy, there is a
3-fold increase in apoptosis in ductal and alveolar cells from Tgf/1 heterozygote compared to wild-type
mouse mammary glands (Ewan et al., 2002). Post-pubertal mice in which Tgfbr2 was conditionally
deleted in the mammary gland also exhibit a much higher rate of apoptosis compared to controls
Other reports using cancer cells and/or transgenic mammary tumors support a role for TGFP in the
suppression of apoptosis (Huang et al., 2000; Muraoka et al., 2003). Conditional overexpression of
active TGF 1 in a triple transgenic model expressing Polyomavirus middle T antigen in the mammary
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Muraoka-Cook, Rebecca S.; Shin, Incheol; Yi, Jae Youn; Easterly,Evangeline; Barcellos-Hoff, Mary Helen; Yingling, Jonathan M. et al. Activated type I TGFbeta receptor (Alk5) kinase confers enhancedsurvival to mammary epithelial cells and accelerates mammary tumorprogression, article, January 2, 2005; Berkeley, California. (https://digital.library.unt.edu/ark:/67531/metadc782778/m1/4/: accessed April 26, 2019), University of North Texas Libraries, Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.