V. Craig Jordan, OBE, PhD, DSc, FMedSci Professor of Breast Medical Oncology
Professor of Molecular and Cellular Oncology University of Texas MD Anderson Cancer Center Houston, Texas

Abstract
“The past is never dead It is not even the past.” – William Faulkner

High dose estrogen therapy for the treatment of post-menopausal women with breast cancer was the first treatment shown in clinical trial to rationally treat any cancer. This was the standard of care for post- menopausa l patients for 30 years before the introduction of tamoxifen in the 1970’s. An understanding of how estrogen can be used as an anti-cancer agent has now been deciphered in the laboratory over the past 15 years. Rules have now been established to understand why long term estrogen deprivation can cause selection of new population of estrogen receptor positive breast
cancer cells that can survive without estrogen but are now vulnerable to estrogen induced cell killing. The story of understanding estrogen induced apoptosis in the laboratory is consistent with clinical observations. In the laboratory, estrogen induced apoptosis is a prolonged process completely unlike cell killing with cytotoxic chemotherapy. The estrogen receptor is the dominant signal transduction pathway in estrogen induced apoptosis, and the events to cause apoptosis are triggered by the shape of the estrogen receptor complex. This slows down apoptosis from hours into days. Estrogen induced apoptosis produces an inflammatory response in the estrogen deprived breast cancer cell. This inflammatory response can be blocked by steroidal glucocorticoids. This discovery by Jordan’s laboratory opened the door to understanding why the estrogen only trial of the Women’s Health Initiative caused a decrease in breast cancer, but the trial using a combination of estrogen medroxyprogesterone acetate (MPA) caused an increase in breast cancer. Jordan discovered that the glucocorticoid like properties of MPA stopped estrogen induced apoptosis in the estrogen deprived cells. This research now opens the door to the opportunity of developing of hormone replacement therapies for women that contain not only estrogen, but also a synthetic progestin that will protect the women’s uterus from the effects of continuous estrogen therapy, thereby lowering the risk of endometrial cancer, but have estrogen-like actions to reinforce estrogen killing breast cancer cells.

Recommended Reading
Sweeney, E.E., Fan, P., Jordan, V.C. (2014) Molecular modulation of estrogen-induced apoptosis by synthetic progestins in hormone replacement therapy: An insight into the Women’s Health Initiative study Cancer Research. (Selected for Faculty 1000 Prime)74:7060-8

Jordan, V. C. (2015). The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer. Endocrine-Related Cancer. 22:Rl -R31