Abstract
Members of the Transforming Growth Factor-β (TGF-β) 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-β
growth response pathway are considered to be tumor suppressor genes, as absence of
one or more of TGF-β 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 (EGA) provides an excellent paradigm to study
the changes that accompany loss of TGF-β-mediated growth, control as a function of
neoplastic development, since it is generally preceded by complex hyperplasia. Type
IECA 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-β 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-β 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-β by incurring defects in every aspect of the pathway that mediates the TGF-β
growth inhibitory response, and 3) describe the putative role for TGF-β in the oncogenesis
of ECA, provided primarily by the results from our laboratory. Understanding the molecular
events involved in TGF-β function in normal cells and its lack of function in tumor
cells should identify novel therapeutic targets in human cancers.
Keywords:
Primary cultures - growth inhibition - gonadal steroids - human cancers
