Loss of growth regulation by transforming growth factor-beta (TGF-beta) inhuman cancers: Studies on endometrial carcinoma

Members of the Transforming Growth Factor-beta (TGF-beta) family are one of the few endogenous inhibitors of cell growth. As uncontrolled cellular pro liferation is a hallmark of cancer, an important question to address is how cancer cells escape normal growth regulatory mechanisms to become malignan t. 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-b eta receptor and signaling proteins cause loss of cell growth regulation th rough an inability to regulate proteins that directly block cells in G1 pha se of the cell cycle. Endometrial carcinoma (ECA) provides an excellent par adigm to study the changes that accompany loss of TGF-beta-mediated growth, control as a function of neoplastic development, since it is generally pre ceded by complex hyperplasia. Type I ECA is characterized as an estrogen-in duced cancer, which responds well to progestin therapy. Since it has become increasingly evident that steroids can regulate growth through growth fact ors, ECA is also an ideal model for investigating the role for gonadal ster oids in the loss of TGF-beta growth regulation in the etiopathogenesis of E CA. Thus, hormonal carcinogenesis adds another level of complexity in study ing 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 fu nctions including its activation, receptors, signal transduction mechanisms , and control of the cell cycle. 2) present recent information that shows h ow malignant cells subvert the growth inhibitory effects of TGF-beta by inc urring defects in every aspect of the pathway that mediates the TGF-beta gr owth inhibitory response, and 3) describe the putative role for TGF-beta in the oncogenesis of ECA, provided primarily by the results from our laborat ory. Understanding the molecular events involved in TGF-beta function in no rmal cells and its lack of function in tumor cells should identify novel th erapeutic targets in human cancers.