Abstract
Estrogens are considered to act as promoters in a multistep process of hormonal carcinogenesis, although the molecular mechanisms by which these hormones act in tumorigenesis are unclear at present. Estradiol is known to induce expression of certain proto‐oncogenes, and this led us to examine potential regulatory regions of the cellular c‐fos oncogene. The 5′‐flanking region of the murine c‐fos contains a 13‐bp palindromic sequence (GGTCTnnnAGACC) with striking homology to the consensus estrogen‐responsive element (ERE) GGTCAnnnTGACC. However, the c‐fos sequence did not bind the human estrogen receptor or confer hormonal responsiveness in a yeast‐based transcriptional test system. Importantly, a single base change in the fifth position of the c‐fos sequence (GGTCTnnnAGACC to GGTCA/GnnnAGACC) produced an element that bound the estrogen receptor and conferred estrogen‐dependent transcriptional activation of a reporter gene. This suggests a specific hypothesis by which estrogens could act as tumor promoters. In this paradigm, the regulatory region of the cellular oncogenes, tumor suppressor genes, and growth‐factor genes contain inactive sequences with close homologies to hormone‐responsive elements. Initiation occurs when some agent (e.g., a chemical carcinogen) causes a mutation in such a sequence to create a functional hormone‐responsive element. Estrogens, acting through their receptors and the mutated element, can then activate the target gene to stimulate cell proliferation and increase the population of initiated cells.
