DIRECT ACTION OF ESTROGEN ON SEQUENCE OF PROGRESSION OF HUMAN PRENEOPLASTIC BREAST DISEASE

We have used the MCF10AT xenograft model of human proliferative breast disease to examine the early effects of estradiol exposure on morphol ogical progression of preneoplastic lesions and to define the step(s) in the morphological sequence at which estrogen may act, The effects o f estradiol on neoplastic progression of estrogen-receptor-positive MC F10AT cells in the orthotopic site were examined in ovariectomized fem ale nude mice that received subcutaneous administration of implants of 17 beta-estradiol or placebo pellets, At 10 weeks, histological analy sis of the lesions derived from the estrogen-supplemented group reveal ed that 92% of lesions displayed histological features of atypical hyp erplasia, carcinoma in situ, or invasive carcinoma, and the remaining 8% exhibited histological features of moderate hyperplasia. These high ly proliferative lesions are in marked contrast to the control group i n which 60% of samples displayed no evidence of hyperplasia, In contra st with control xenografts, estrogen-exposed xenografts demonstrated e xtensive areas of papillary growth, adenosis-like areas, prominent hos t inflammatory infiltration, and angiogenesis, Our results suggest tha t estrogen exerts a growth-promoting effect on benign or premalignant ductal epithelium by enhancing 1) the frequency of lesion formation, 2 ) the size of lesions, 3) the speed of transformation from normal/mild hyperplasia to those with atypia, 4) the degree of dysplasia, and 5) angiogenesis.