Of the 175,000 women diagnosed with breast cancer yearly, one-half to two-thirds will relapse after surgery, many after receiving adjuvant antiestrogen therapy. Development of hormone-resistance at this stage would be expected and yet, many respond to secondary hormonal therapies. The changes in tumor biology allowing additional responses are, as yet, uncharacterized. Based upon in vitro and in vivo data, we hypothesize that breast tumor cells, when deprived of estrogens, increase their level of sensitivity through adaptive or cell selective mechanisms. This hypothesis has the important therapeutic implication that more complete inhibition of estrogen action or synthesis than currently possible would be beneficial under conditions of enhanced estradiol sensitivity. This proposal seeks to characterize the process of altered estradiol responsivity, determine its mechanism, examine its effects on tumor aggressiveness, and develop means to more effectively inhibit estrogen biosynthesis. Specifically, we will characterize the altered sensitivity of long-term estrogen-deprived human breast cancer cells in culture and determine whether the enhanced effects on proliferation are mediated by increased growth factor expression or sensitivity. We will identify the biologic mechanisms which mediate enhanced sensitivity to estrogens or increased local production to estradiol by comparing several parameters in wild-type and long-term estradiol-deprived MCF-7 cells. These include estradiol uptake into cells, estrogen receptor functionality, estrogen receptor phosphorylation, nuclear binding characteristics of the estrogen receptor, levels of gene transcription and magnitude of in situ estradiol biosynthesis. The biological characteristics of breast tumors from untreated patients will compared with those previously treated with estrogen ablative therapy. These studies will examine the sensitivity to estradiol by clonogenic assays in soft agar, the structural and functional alterations of he estrogen receptor, and the ability of tumors to synthesize estradiol in situ. Finally, we will utilize a highly potent aromatase inhibitor, CGS 20267, to enhance estradiol suppression in pre- and postmenopausal patients previously treated with antiestrogens or estrogen ablative therapy. These studies should provide insight into the mechanisms of tumor biologic changes during therapy and develop practical means of improving therapy in patients relapsing after initial mastectomy.
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