Transforming growth factor-beta and breast cancer: Transforming growth factor-β/SMAD signaling defects and cancer

The transforming growth factor-β (TGF-β) family of polypeptide growth factors regulates cellular processes, including cell division, differentiation, motility, adhesion, and death, in virtually all tissues ([1] and references therein). TGF-β is an important regulator of normal mammary gland development and function, as well as of the development and progression of breast tumors. TGF-β potently inhibits cell cycle progression of epithelial cells, including those of the lobules and ducts of the mammary gland, and it thereby controls epithelial cell proliferation and regression during mammary gland development, and during and after lactation in the adult gland [2].In breast cancer, TGF-β has been suggested to play a dual role [3]. It acts as a tumor suppressor in early stages of the disease when it inhibits the outgrowth of carcinomas in situ via its antiproliferative functions. This has been demonstrated in transgenic mouse models, in which over expression of TGF-β1 (one isoform of TGF-β) is targeted to the mammary gland, and tumor formation is induced by concomitant over-expression of TGF-β and administration of a chemical carcinogen [4]. In later stages of the disease, TGF-β is believed to promote tumor progression, in part by enhancing tumor cell motility and invasiveness [5,6] and the capacity to form metastases [6,7,8]. Tumor promoting functions of TGF-β correlate with increased secretion of TGF-β by the cancer cells during tumor progression [3].This apparent switch of the role of TGF-β in the regulation of tumorigenesis is reflected in changes of tumor cell responsiveness. Similar to other types of carcinomas, many malignant breast carcinoma cells have lost most or all sensitivity to TGF-β-induced growth inhibition, while tumor cells derived from early stages of the disease are usually inhibited [9]. This loss of antiproliferative responsiveness thereby predisposes to or causes cancer progression.TGF-β induces growth inhibition by arresting cells in the G1 phase