27 - 30 May 2005

PROGESTERONE INHIBITION OF ENDOMETRIAL CANCER CELL GROWTH Kimberly K. Leslie MD Professor and Director Reproductive Molecular Biology Laboratory The Department of Obstetrics and Gynecology Co-Director Women’s Cancer Program The University of New Mexico Health Sciences Center Albuquerque, NM USA

Numerous lines of evidence link endometrial cancer with estrogen stimulation unopposed by the differentiating effects of progesterone. The role of progesterone in the glandular epithelium of the endometrium is primarily antagonistic to estrogen-mediated cell proliferation (1); this is in contrast to the breast, where progesterone mediates both proliferative and anti-proliferative effects. Therefore, the study of progestin action in the endometrium has particular importance because the epithelium relies on progesterone to induce cell differentiation and to counter uncontrolled growth.

Our work has focused on the downstream genomic and proteomic effects of progesterone through PRA and PRB (2) that inhibit endometrial cancer proliferation, induce apoptosis and differentiation, and prevent metastatic spread (3-7). We have identified a group of genes, including cell adhesion molecules, cytokines, growth factors (such as the epidermal growth factor), DNA remodeling proteins, and other transcription factors that are controlled by, and in turn control, progesterone’s actions in the endometrium. These pathways are now being exploited as new therapeutic avenues in endometrial cancer clinical trials.

While progestins alone have been used with great success to reverse pre-malignant endometrial hyperplasia, they are not consistently effective in the treatment of endometrial cancer – response rates are typically below 25% and are transient. Progestin resistance is related to loss of PR and the compensatory activation of escape pathways.

Combination regimens, such as tamoxifen (to induce PR) plus intermittent progestin and biologics such as tyrosine kinase inhibitors and/or mTOR inhibitors plus progestin, offer new promise to prolong the beneficial effects of hormonal therapy.

References:

1. Clarke CL, Sutherland RL. Progestin regulation of cellular proliferation. Endocr Rev 1990;11(2):266-301.

2. Leslie KK, Stein MP, Kumar NS, Dai D, Stephens J, Wandinger-Ness A, et al. Progesterone receptor isoform identification and subcellular localization in endometrial cancer. Gynecol Oncol 2005;96(1):32-41.

3. Dai D, Kumar NS, Wolf DM, Leslie KK. Molecular tools to reestablish progestin control of endometrial cancer cell proliferation. Am J Obstet Gynecol 2001;184(5):790-7.

4. Dai D, Litman ES, Schonteich E, Leslie KK. Progesterone regulation of activating protein-1 transcriptional activity: a possible mechanism of progesterone inhibition of endometrial cancer cell growth. J Steroid Biochem Mol Biol 2003;87(2-3):123-31.

5. Dai D, Wolf DM, Litman ES, White MJ, Leslie KK. Progesterone inhibits human endometrial cancer cell growth and invasiveness: down-regulation of cellular adhesion molecules through progesterone B receptors. Cancer Res 2002;62(3):881-6.

6. Davies S, Dai D, Feldman I, Pickett G, Leslie KK. Identification of a novel mechanism of NF-kappaB inactivation by progesterone through progesterone receptors in Hec50co poorly differentiated endometrial cancer cells: induction of A20 and ABIN-2. Gynecol Oncol 2004;94(2):463-70.

7. Davies S, Dai D, Wolf DM, Leslie KK. Immunomodulatory and transcriptional effects of progesterone through progesterone A and B receptors in Hec50co poorly differentiated endometrial cancer cells. J Soc Gynecol Investig 2004;11(7):494-9.

List of abstracts from the 3rd International Conference on the Female Reproductive Tract