Skp2B Stimulates Mammary Gland Development by Inhibiting REA, the Repressor of the Estrogen Receptor

Abstract

Skp2B, an F-box protein of unknown function, is frequently overexpressed in breast cancer. In order to determine the function of Skp2B and whether it has a role in breast cancer, we performed a two-hybrid screen and established transgenic mice expressing Skp2B in the mammary glands. We found that Skp2B interacts with the repressor of estrogen receptor activity (REA) and that overexpression of Skp2B leads to a reduction in REA levels. In the mammary glands of MMTV-Skp2B mice, REA levels are also low. Our results show that in virgin transgenic females, Skp2B induces lobuloalveolar development and differentiation of the mammary glands normally observed during pregnancy. As this phenotype is identical to what was observed for REA heterozygote mice, our observations suggest that the Skp2B-REA interaction is physiologically relevant. However, in contrast to REA^+/− mice, MMTV-Skp2B mice develop mammary tumors, suggesting that Skp2B affects additional proteins. These results indicate that the observed expression of Skp2B in breast cancer does contribute to tumorigenesis at least in part by modulating the activity of the estrogen receptor.

We thank Liliana Ossowski, who provided us with invaluable comments during the course of this work. We also thank Shabnam Jaffer, who provided us with her pathological expertise, and Ramla Benmaamar for Fig. 1D.

We dedicate this work to the memory of Rafael Mira-Lopez, who was a fine mammary gland biologist and a wonderful man.

All authors declare that they have no commercial affiliation and no conflict of interest related to this publication. This work was supported by NIH RO1 grant no. CA109482 to D.G. and by the Samuel Waxman Cancer Research Foundation.