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J. Biol. Chem., Vol. 279, Issue 24, 25503-25510, June 11, 2004

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Human Chorionic Gonadotropin Decreases Proliferation and Invasion of Breast Cancer MCF-7 Cells by Inhibiting NF-B and AP-1 Activation^*

Ch. V. Rao, X. Li, S. K. Manna¶, Z. M. Lei, and B. B. Aggarwal¶

From the Department of Obstetrics, Gynecology and Women's Health, University of Louisville Health Sciences Center, Louisville, Kentucky 40292 and the ^¶Cytokine Research Laboratory, Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The epidemiological data suggest that breast cancer risk decreases in women who complete full-term pregnancy at a young age. Studies on a rat breast cancer model indicate that human chorionic gonadotropin (hCG), a hormone that is present in very high levels during pregnancy, could be responsible for this decrease. These findings, as well as those demonstrating the presence of functional luteinizing hormone (LH)/hCG receptors in human breast cells, prompted us to investigate the anti-proliferative and anti-invasive effects of hCG in human breast cancer MCF-7 cells by down-regulating NF-B and AP-1 transcription factors. Treatment of MCF-7 cells with highly purified hCG resulted in a modest dose-dependent and hormone-specific decrease in cell proliferation. hCG treatment also decreased cell invasion, which was more dramatic than the decrease in cell proliferation. These hCG actions were abrogated when receptor synthesis was inhibited by treatment with antisense hCG/LH receptor phosphorothioate oligodeoxynucleotide. hCG treatment prevented the tumor necrosis factor-dependent NF-B and AP-1 activation, which paralleled a decrease in the phosphorylation and degradation of IB. The findings that hCG treatment increased cAMP synthesis and activated cAMP-dependent protein kinase, dibutyryl cAMP mimicked hCG in preventing NF-B activation, and dideoxyadenosine, an adenylate cyclase inhibitor, prevented the hCG effect on NF-B suggested that the hCG actions are mediated via the cAMP-dependent protein kinase A signaling pathway. In summary, our results demonstrate that hCG has anti-proliferative and anti-invasive effects in MCF-7 cells by down-regulating NF-B and AP-1. These findings support the premise that hCG could be responsible for the pregnancy-induced protection against breast cancer in women.

Received for publication, January 21, 2004 , and in revised form, March 9, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Division of Research, Dept. of Obstetrics, Gynecology and Women's Health, 438 MDR Bldg., 511 South Floyd St., University of Louisville Health Sciences Center, Louisville, KY 40292. Tel.: 502-852-5688, 502-852-6198; Fax: 502-852-0881; E-mail: cvrao001{at}gwise.louisville.edu.

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