Progestins in Hormone Replacement Therapies Reactivate Cancer Stem Cells in Women With Preexisting Breast Cancers: A Hypothesis

Abstract

An increased risk of invasive, estrogen receptor-positive (ER+) breast cancer in the combined estrogen plus progestin arm of the Women's Health Initiative menopausal hormone replacement therapy (HRT) trial was in large part responsible for stopping the study prematurely in 2002. Subsequent studies offered several possibilities to explain how addition of progestins to estrogens increases the risk of breast cancer. The authors of this report offer a hypothesis for the increased risk based on their research and that of other investigators. A rare small tumorigenic subpopulation of estrogen receptor-negative, progesterone receptor-negative cancer stem cells is present in experimental ER+, progesterone receptor-positive human breast cancers. Progestins but not estrogens act on the ER+, progesterone receptor-positive differentiated cells (especially in small nascent tumor colonies) to reactivate and revert to the more primitive estrogen receptor-negative, progesterone receptor-negative stem cells without requiring proliferation. The authors propose that a reservoir of occult, undetected, preinvasive breast cancer or dormant breast cancer stem cells is present before the start of estrogen plus progestin therapy in some women. Autopsy data of women over 40 years of age who did not have known breast cancer during life showed that the median prevalence of invasive breast cancer at death was 1.3% (range: 0%–1.8%), and the median prevalence of ductal carcinoma in situ was 8.9% (range: 0%–14%). Estrogens are not involved in the activation process, but once receptors are reacquired, they can act through their mitogenic properties to expand the tumor cell population. The authors believe that improved screening methods are needed to detect occult, possibly dormant, breast cancers before initiation of hormone replacement therapy. If the hypothesis is correct, women with such preexisting malignancies should be excluded from regimens containing systemic progestins.