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.

Skp2B Overexpression Alters a Prohibitin-p53 Axis and the Transcription of PAPP-A, the Protease of Insulin-Like Growth Factor Binding Protein 4

“…Of particular interest, are the reports that prohibitin is required for the transcriptional activity of p53 [7], [8] since deregulation of p53 is a likely candidate that may contribute to the mammary gland carcinoma observed in MMTV-Skp2B mice [2]. Indeed, we also reported that Skp2B overexpressing cells show a defect in the transcriptional activity of p53 both in vitro and in vivo [4].…”

“…Elevation in PAPP-A represents therefore a likely candidate for the elevation in IGFBP-4 cleavage we had observed [2]. As the antibodies against PAPP-A recognized human PAPP-A but not mouse PAPP-A, we used RT-PCR to determine the levels of PAPP-A in mice.…”

“…We found that MMTV-Skp2B mice develop a number of phenotypes including acceleration of the invasion of the fat pad during puberty, increased side branching, pregnancy-like phenotype in virgin females and mammary tumors [2].…”

Roles of F-box proteins in cancer

“…Moreover, transgenic mice expressing Skp2 in the T-lymphoid lineage and co-expressing Nras developed T cell lymphomas with shorter latency and showed decreased survival 77 . Transgenic mice that expressed the SKP2 splice variant SKP2B under the control of the (MMTV promoter) develop mammary tumours, partly through the downregulation of REA (also known as prohibitin 2), which is an inhibitor of the oestrogen receptor 78 . Consistent with a crucial oncogenic role for SKP2, Skp2 -knockout mice are resistant to the development of sarcomas and lymphomas in an Arf −/− background, and are resistant to adrenal and prostate cancers when the tumour suppressor gene Pten is lost 79 .…”

Prohibitin Ligands in Cell Death and Survival: Mode of Action and Therapeutic Potential

“…p53 is a tumor suppressor that controls the cell cycle, apoptosis, genomic stability, and angiogenesis (Chander et al, 2010(Chander et al, , 2011Fusaro et al, 2003;Joshi et al, 2007). A component of ubiquitin ligase complexes, Skp2B, which is overexpressed in many breast cancers, interacts with both PHB1 and PHB2 to promote their degradation (Chander et al, 2010(Chander et al, , 2011Umanskaya et al, 2007). Because PHB1 acts as an activator (Fusaro et al, 2003) and chaperone (Chander et al, 2011) for p53, this depletion in PHB1 leads to an attenuated activity of p53 in cancer cells overexpressing Skp2B and consequently promotes their survival.…”