Women with estrogen receptor positive breast cancers frequently respond initially to inhibition of estrogen secretion or action but later relapse. Secondary therapies designed to further lower estrogen levels induce additional remiss ions but progression to a hormone refractory state invariably follows. The mechanisms mediating these secondary responses and later progression are incompletely understood. Based upon our priOr studies, we have develOped an overall hypothesis to explain these observations. We postulate that tumor cells can adapt to conditions of estrogen deprivation by developing enhanced sensitivity to estrogens or to their precursor substrates. Using a model system of long term estrogen withdrawal, we directly demonstrated the ability of cells to develop hypersensitivity to estradiol. The enhanced sensitivity results in two biologic effects: a stimulation of cells at 4 log lower concentrations of estradiol and a paradoxical inhibition with a similar left shift in dose response. Remarkable was the observation that the hypersensitivity phenotype can be induced and then reverted back to basal over a two year period by manipulating the levels of estrogen exposure. The mechanisms involved in development of hypersensitivity are unknown but could be the same as those leading to-progression to a hormone resistant state. The proposed studies are based upon the working hypothesis that ligand independent activation of the estrogen receptor serves to enhance sensitivity to estradiol The resultant increase in cell proliferation may be mediated through the transcription factor c- myb. Enhanced sensitivity to estrogen precursor substrates contributes to this adaptive process. Our investigative strategy involves testing of specific components of this hypothesis using our in vitro model for examining precise biochemical steps, a xenograft system for validation of findings in vivo, and breast tumors from women deprived of estrogen. Firstly, we will examine ligand independent receptor activation. Our strategy is to block specific pathways in order to cause reversion of hypersensitive cells back to a normal state and to induce hypersensitivity in wild type cells by activating steps found to be critical. As biologic endpoints, we will examine estrogen receptor mediated transcription and Cellular growth. We will focus upon involvement of the growth factor, MAP kinase, PKA and PKC pathways as mediators of ligand independent receptor activation. Secondly, we will test the hypothesis that c.myb acts as a downstream mediator of estrogen effects on cell proliferation in long term estradiol deprived and in wild type MCF-7 breast cancer cells. Thirdly, we will test the hypothesis that long term estradiol deprivation enhances sensitivity to estrogen precursors by increasing their enzymatic conversion to active estrogens. These studies will provide insight into the sequential process of progression of tumors from hormone sensitive, to hypersensitive, to hormone independent. We expect our findings to identify potential new therapeutic targets for prevention of tumor progression; to gain insight into new sequential approaches to hormonal therapy, and to provide a back round for the possibility of intermittent hormonal therapy.
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