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J. Biol. Chem., Vol. 278, Issue 51, 51703-51712, December 19, 2003

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Mullerian Inhibiting Substance Promotes Interferon -induced Gene Expression and Apoptosis in Breast Cancer Cells^*

Yasunori Hoshiya, Vandana Gupta, Hirofumi Kawakubo, Elena Brachtel, Jennifer L. Carey, Laura Sasur, Andrew Scott, Patricia K. Donahoe, and Shyamala Maheswaran

From the Pediatric Surgical Research Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

This report demonstrates that in addition to interferons and cytokines, members of the TGF superfamily such as Mullerian inhibiting substance (MIS) and activin A also regulate IRF-1 expression. MIS induced IRF-1 expression in the mammary glands of mice in vivo and in breast cancer cells in vitro and stimulation of IRF-1 by MIS was dependent on activation of the NFB pathway. In the rat mammary gland, IRF-1 expression gradually decreased during pregnancy and lactation but increased at involution. In breast cancer, the IRF-1 protein was absent in 13% of tumors tested compared with matched normal glands. Consistent with its growth suppressive activity, expression of IRF-1 in breast cancer cells induced apoptosis. Treatment of breast cancer cells with MIS and interferon (IFN-) co-stimulated IRF-1 and CEACAM1 expression and synergistic induction of CEACAM1 by a combination of MIS and IFN- was impaired by antisense IRF-1 expression. Furthermore, a combination of IFN- and MIS inhibited the growth of breast cancer cells to a greater extent than either one alone. Both reagents alone significantly decreased the fraction of cells in the S-phase of the cell cycle, an effect not enhanced when they were used in combination. However, MIS promoted IFN--induced apoptosis demonstrating a functional interaction between these two classes of signaling molecules in regulation of breast cancer cell growth.

Received for publication, July 15, 2003 , and in revised form, October 1, 2003.

^* This work was supported by the Surdna fellowship fund from the Department of Surgery, Massachusetts General Hospital (to Y. H.), Department of Defense Breast Cancer Research Grant DAMD17-03-1-0407 (to V. G.), Grants HD32112 and CA17393 from NICHD and NCI, National Institutes of Health, respectively (to P. K. D.), and by the Breast Cancer Research Grant from the Massachusetts Department of Public Health, the Avon Breast Cancer Pilot Project Grant, the Claflin Distinguished Scholar Award, partial support from the Dana-Farber Harvard Breast Cancer SPORE, and from NCI, National Institutes of Health Grant CA89138-01A1 (to S. M.). 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: Pediatric Surgical Research Laboratories, WRN1024, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114. Tel.: 617-724-6552; Fax: 617-724-7221; E-mail: maheswaran{at}helix.mgh.harvard.edu.

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