Loss of growth regulation by transforming growth factor-beta (TGF-beta) in human cancers: studies on endometrial...

Members of the Transforming Growth Factor-beta (TGF-beta) family are one of the few endogenous inhibitors of cell growth. As uncontrolled cellular proliferation is a hallmark of cancer, an important question to address is how cancer cells escape normal growth regulatory mechanisms to become malignant. In this context, components of the TGF-beta growth response pathway are considered to be tumor suppressor genes, as absence of one or more of TGF-beta receptor and signaling proteins cause loss of cell growth regulation through an inability to regulate proteins that directly block cells in G1 phase of the cell cycle. Endometrial carcinoma (ECA) provides an excellent paradigm to study the changes that accompany loss of TGF-beta-mediated growth, control as a function of neoplastic development, since it is generally preceded by complex hyperplasia. Type 1 ECA is characterized as an estrogen-induced cancer, which responds well to progestin therapy. Since it has become increasingly evident that steroids can regulate growth through growth factors, ECA is also an ideal model for investigating the role for gonadal steroids in the loss of TGF-beta growth regulation in the etiopathogenesis of ECA. Thus, hormonal carcinogenesis adds another level of complexity in studying loss of growth regulation in human cancers. The purpose of this review is to 1) provide the most current background information on how TGF-beta functions including its activation, receptors, signal transduction mechanisms, and control of the cell cycle. 2) present recent information that shows how malignant cells subvert the growth inhibitory effects of TGF-beta by incurring defects in every aspect of the pathway that mediates the TGF-beta growth inhibitory response, and 3) describe the putative role for TGF-beta in the oncogenesis of ECA, provided primarily by the results from our laboratory. Understanding the molecular events involved in TGF-beta function in normal cells and its lack of function in tumor cells should identify novel therapeutic targets in human cancers.