Transforming growth factor-beta and breast cancer: Cell cycle arrest by transforming growth factor-β and its disruption in cancer

TGF-β is a potent inhibitor of mammary epithelial cell proliferation [1,2] and regulates mammary development in vivo [3,4,5]. Mammary-specific overexpression of TGF-β in transgenic mice can induce mammary hypoplasia and inhibit tumourigenesis [6,7,8]. Although normal human mammary epithelial cells (HMECs) are exquisitely sensitive to TGF-β [9], human breast cancer lines require 10-fold to 100-fold more TGF-β to produce an antimitogenic response, and some show complete loss of this effect [10].Although loss of growth inhibition by TGF-β in human cancers can arise through loss of TGF-β production or through mutational inactivation of the TGF-β receptors and Smad signalling molecules [11,12], these defects are not observed in most arrest-resistant cancer lines. This observation, and the frequent appearance of resistance to more than one inhibitory cytokine in human tumours [13] emphasize the importance of the cell cycle effectors of growth arrest induced by TGF-β as targets for inactivation in cancer.TGF-β can either lengthen G1 transit time or cause arrest in late G1 phase [14]. This cell cycle arrest is usually reversible [15,16], but in some cases is associated with terminal differentiation [17,18,19]. Because TGF-β arrests susceptible cells in the G1 phase, a brief review of cell cycle regulation is presented. This is followed by a review of the multiple and often, complementary mechanisms that contributing to G1 phase arrest by TGF-β and of how they are disrupted in breast and other cancers.Cell cycle progression is governed by cdks, which are activated by cyclin binding [20,21] and inhibited by the cdk inhibitors [22,23]. The cdks integrate mitogenic and growth inhibitory signals and coordinate cell cycle transitions [24,25]. G1 to S phase progression is regulated by D-type cyclin-, E-type cyclin- and cyclin A-associated cdks (Fig. 1). B-type cyclin-associated kinases govern G2 and M phases. Both E-type and D-type cyclin-cdks contribute to phosphorylation of the