Molecular and Cellular Biology
The Estrogen/Progesterone Paradox in the Development of Breast Cancer
Daniel Medina, Ph.D., has been studying the paradoxical effects of estrogen and progesterone in the development of breast cancer. Pregnancy, or estrogen and progesterone, induces a long term protection against breast cancer in humans, rat and mouse models. Dr. Medina and his colleagues initially demonstrated that this protective effect occurs in mouse models, and using the p53 null model demonstrated the obligatory role of a specific gene underlying this protective effect. Recent studies have provided strong evidence for an effect of hormones that is mediated via systemic or mammary stromal pathways. Subsequent studies in human breast tissues are investigating surrogate markers for the protective effect that can be used in clinical studies. Paradoxically, long term exposure to estrogen and progesterone promotes premalignant mammary progression to malignancy. Dr. Medina and his colleagues have used the p53 null mammary model to investigate the role of hormone antagonists to prevent the development of both estrogen receptor (ER)-positive and ER-negative tumors. Their initial studies used tamoxifen to block premalignant progression. These studies demonstrated tamoxifen was just as effective as ovariectomy in blocking premalignant progression, including the appearance of ER-negative tumors. Current studies are testing the combination of low doses of tamoxifen with other chemopreventive agents in order to provide a solid rationale for subsequent clinical studies.
Dr. Medina’s nomination was based on the following publications:
Medina D, Kittrell FS. p53 function is required for hormone-mediated protection of mouse mammary tumorigenesis. Cancer Res. 2003 Oct 1;63(19):6140-3.
Pati D, Haddad BR, Haegele A, Thompson H, Kittrell FS, Shepard A, Montagna C, Zhang N, Ge G, Otta SK, McCarthy M, Ullrich RL, Medina D. Hormone-induced chromosomal instability in p53-null mammary epithelium. Cancer Res. 2004 Aug 15;64(16):5608-16.
Medina D, Kittrell FS, Hill J, Shepard A, Thordarson G, Brown P. Tamoxifen inhibition of estrogen receptor-alpha-negative mouse mammary tumorigenesis. Cancer Res. 2005 Apr 15;65(8):3493-6.