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J. Biol. Chem., Vol. 278, Issue 47, 47319-47325, November 21, 2003

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Induction of Mammary Gland Differentiation in Transgenic Mice by the Fatty Acid-binding Protein MRG^*

Mingsheng Wang, Yiliang E. Liu, Itzhak D. Goldberg, and Y. Eric Shi

From the Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for The Albert Einstein College of Medicine, New Hyde Park, New York 11040

A mammary-derived growth inhibitor-related gene (MRG) was previously identified and characterized. MRG induces differentiation of mammary epithelial cells in vitro and its expression is associated with mammary differentiation. To further define the role of MRG on mammary gland differentiation, a MRG transgenic mice model under the control of mouse mammary tumor virus promoter was established and the effect of MRG on mammary gland differentiation was investigated at histological and molecular levels. Expression of endogenous mouse MRG gene was significantly increased from the non-differentiated gland of control virgin mice to the functionally differentiated gland of pregnant control mice. Whole mount analyses demonstrated that ductal development was not affected by MRG transgene expression. While there was no lobuloalveolar structure in control virgin mice, expression of MRG transgene in the mammary gland resulted in the development of lobuloalveolar-like structure, which mimics the gland from early pregnancy. Consistent with the morphological change, expression of MRG also increased milk protein -casein expression in the gland. To study the mechanism of MRG-induced mammary differentiation, we investigated the Stat5 activation in the glands from the transgenic mouse versus virgin control mouse. While activated Stat5 was expressed at the minimal level in the non-differentiated control virgin gland, a significant Stat5 phosphorylation was observed in the virgin transgenic gland. Our data indicate that MRG is a mediator of the differentiating effects of pregnancy on breast epithelium, and overexpression of MRG in young nulliparous mice can induce differentiation.

Received for publication, July 25, 2003 , and in revised form, August 25, 2003.

^* This work was supported in part by Grant CA93542-2 from the National Institutes of Health and Grant DAMD17-01-1-0353 (Postdoctoral Fellowship Award) from the United State Army Breast Cancer Research Program. 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: Dept. of Radiation Oncology, Long Island Jewish Medical Center, New Hyde Park, NY 11040. Tel.: 718-470-3086; Fax: 718-470-9756; E-mail: shi{at}lij.edu.

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