COMPARISON OF ESTROGEN-RECEPTOR DNA-BINDING IN UNTREATED AND ACQUIREDANTIESTROGEN-RESISTANT HUMAN BREAST-TUMORS

Preliminary studies have suggested that measuring the ability of immun oreactive 67-kDa estrogen receptor (ER) to bind DNA and form in vitro complexes with its cognate estrogen response element (ERE) might serve to identify breast tumors most likely to respond to antiestrogens lik e tamoxifen. Data from two different surveys of untreated primary brea st tumors confirmed that only 67% (74 of 111) of ER-positive tumors ex press a receptor capable of forming ER-ERE complexes by gel-shift assa y, with tumors of lower ER content having significantly reduced ER DNA -binding frequency (56%) relative to those of higher ER content (82%; P = 0.007). In contrast to these untreated tumors, a panel of 41 recep tor-positive breast tumors excised after acquiring clinical resistance to tamoxifen during either primary (n = 26) or adjuvant therapy (n = 15) showed a significantly greater ER DNA-binding frequency, with near ly 90% capable of forming ER-ERE complexes (P < 0.02). To assess exper imentally whether ER DNA-binding function is altered during the develo pment of antiestrogen resistance, nude mouse MCF-7 tumor xenografts we re analyzed before and after the acquisition of in vivo resistance to either tamoxifen or a pure steroidal antiestrogen, ICI 182,780. Tamoxi fen-resistant MCF-7 tumors retained full expression of 67-kDa DNA-bind ing ER, and despite a markedly reduced ER content in the ICI 182,780-t reated tumors, the expressed ER in these antiestrogen-resistant tumors exhibited full ability to form ER-ERE complexes. These findings indic ate that breast tumors with acquired antiestrogen resistance continue to express ER of normal size and DNA-binding ability and suggest that the failure of antiestrogens to arrest tumor growth during emergence o f clinical resistance results from an altered gene-regulatory mechanis m(s) other than ER-ERE complex formation.