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 morphological progression of preneoplastic lesions and to define the step(s) in the morphological sequence at which estrogen may act. The effects of estradiol on neoplastic progression of estrogen-receptor-positive MCF10AT cells in the orthotopic site were examined in ovariectomized female nude mice that received subcutaneous administration of implants of 17beta-estradiol or placebo pellets. At 10 weeks, histological analysis of the lesions derived from the estrogen-supplemented group revealed that 92% of lesions displayed histological features of atypical hyperplasia, carcinoma in situ, or invasive carcinoma, and the remaining 8% exhibited histological features of moderate hyperplasia. These highly proliferative lesions are in marked contrast to the control group in which 60% of samples displayed no evidence of hyperplasia. In contrast with control xenografts, estrogen-exposed xenografts demonstrated extensive areas of papillary growth, adenosis-like areas, prominent host inflammatory infiltration, and angiogenesis. Our results suggest that 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.