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[Cancer Research 62, 881-886, February 1, 2002]
© 2002 American Association for Cancer Research

Tumor Biology

Progesterone Inhibits Human Endometrial Cancer Cell Growth and Invasiveness

Down-Regulation of Cellular Adhesion Molecules through Progesterone B Receptors1

Donghai Dai, Douglas M. Wolf, Elizabeth S. Litman, Michael J. White and Kimberly K. Leslie2

The Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131-5286 [D. D., K. K. L.], and Section of Basic Reproductive Science, Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Denver, Colorado 80262 [D. M. W., E. S. L., M. J. W.]

Progesterone is a critical steroid hormone that controls cell proliferation and differentiation in the female reproductive tract. Progesterone acts through two nuclear receptor isoforms, progesterone receptors A and B (PRA and PRB, respectively), each with unique cellular effects. Loss of PRB has recently been linked to the development of poorly differentiated endometrial tumors, a lethal form of cancer. To study the molecular effects of progesterone, progesterone receptors were introduced into Hec50co endometrial cancer cells by adenoviral vectors encoding either PRA or PRB. Progesterone induced the cyclin-dependent kinase inhibitors p21 and p27, thereby significantly reducing the percentage of proliferating cells. Cancer cell invasion was also markedly inhibited as measured by Matrigel invasion studies. Similarly, a differentiated, secretory phenotype was induced by progesterone in cells expressing PRB. However, replicative senescence was induced by progesterone only in cells expressing PRA. Expression array analysis followed by confirmatory semiquantitative reverse transcription-PCR experiments demonstrated a significant progesterone-dependent inhibition of expression of a cadre of cellular adhesion molecules, including fibronectin, integrin {alpha}3, integrin ß1, integrin ß3, and cadherin 6. The level of down-regulation of adhesion molecule expression was significantly greater in the presence of the B isoform, demonstrating that progesterone acts principally through B receptors to inhibit cancer cell invasiveness modulated by adhesion molecules.




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Copyright © 2002 by the American Association for Cancer Research.