Fifty percent of patients with breast cancer in which estrogen receptors are present and 23% in which both estrogen and progesterone receptors are present fail to respond to hormone therapy. The mechanism of resistance is unknown. Similarly it is not known why tumors that initially respond to hormone manipulation become resistant. Hormone dependent breast tumors secrete growth stimulatory factors into the media in response to estrogen. This conditioned media can substitute the necessity for estrogen to stimulate hormone dependent cells. Hormone independent cells secrete these autocrine factors in higher levels without estrogen stimulation. Human breast tumors have been found to consist of heterogeneous populations of ER+ and ER- cells. The goal of this project is to determine what role autocrine growth factors produced by hormone independent breast cancer cells have on the sensitivity or resistance of hormone dependent cells to anti-estrogens. It will be determined whether these growth factors interfere with the dose response of hormone dependent cells to estrogen and anti-estrogen administration. A variant of the hormone dependent ZR-75-I line resistant to anti- estrogens will be selected and characterized. The presence of estrogen and progesterone receptors and the binding capacities of the variants will be determined. The growth factors produced by the resistant line will be identified and examined for their effect on the response of hormone dependent cells to estrogen and anti- estrogen treatment. the importance of individual growth factors including EGF, insulin, insulin-like growth factors, alpha TGF and beta TGF on the sensitivity of estrogen dependent cells will be determined. The role of alpha TGF will be the first factor to be examined. To determine if the presence of autocrine growth factors facilitates the development of resistance, resistant variants will be selected in the presence of growth factors in higher amounts than found in the conditioned media of hormone dependent cells. These variants will be characterized. Hormone dependent and independent cells will be cloned from primary human breast tumors, and examined for production of autocrine factors that interfere with estrogen and anti-estrogen response. Investigations of the mechanism of growth factor induced hormone resistance will be begun.
