Cause or prevention of breast cancer with estrogens: analysis from tumor biologic data, growth kinetic model and Women’s Health Initiative study

The existing medical literature suggests that estrogens may cause breast cancer but, paradoxically, can also prevent this neoplasm under specific circumstances. Appropriate interpretation of this complex data requires an understanding of emerging concepts of tumor biology. A substantial body of data, including animal models and epidemiologic studies, suggests that estrogens contribute to the development of breast cancer. Additionally, pre-clinical experiments indicate that the responsible mechanisms include both estrogen receptor α-dependent and -independent effects (ERα-dependent and ERα-independent effects). We recently developed two models to describe the growth kinetics of occult breast tumors, one based on autopsy studies and tumor doubling time and the other, computer-based. Validation of the models involved comparison of the predicted incidence of breast cancer with the actual incidence in population-based studies. Utilization of these models allowed us to determine that 16 years on average are required for tumors to undergo the 30 doubling times necessary for the occult tumors to reach the threshold for clinical detection. These models suggest that menopausal hormone therapy with estrogen plus a progestogen in the Women's Health Initiative (WHI) study accelerated the doubling time of occult, pre-existing tumors from 200 to 150 days and thus, increased the rate of tumor diagnosis. Based on estrogen-induced apoptosis data, the model accurately predicted the prevention of diagnosed breast cancer in the estrogen-alone arm of the WHI. Notably, pre-clinical studies demonstrated that conjugated equine estrogen, as used in the WHI, has unique, pro-apoptotic properties compared to the anti-apoptotic effects of estradiol, a finding providing an explanation for the reduction in breast cancer with conjugated equine estrogen.