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SirT1 modulates the estrogen-insulin-like growth factor-1 signaling for postnatal development of mammary gland in mice

Show simple item record Li, Hongzhe en_US Rajendran, Grace K. en_US Liu, Ninning en_US Ware, Carol B. en_US Rubin, Brian P. en_US Gu, Yansong en_US 2010-05-06T20:09:26Z 2010-05-06T20:09:26Z 2007 en_US
dc.identifier.citation Li H, Rajendran G, Liu N, et al. SirT1 modulates the estrogen-insulin-like growth factor-1 signaling for postnatal development of mammary gland in mice. Breast Cancer Research. 2007;9(1):R1. en_US
dc.identifier.other 10.1186/bcr1632 en_US
dc.identifier.uri en_US
dc.description.abstract Introduction: Estrogen and insulin-like growth factor-1 (IGF-1) play important roles in mammary gland development and breast cancer. SirT1 is a highly conserved protein deacetylase that can regulate the insulin/IGF-1 signaling in lower organisms, as well as a growing number of transcription factors, including NF-[kappa]B, in mammalian cells. Whether SirT1 regulates the IGF-1 signaling for mammary gland development and function, however, is not clear. In the present study, this role of SirT1 was examined by studying SirT1-deficient mice. Methods: SirT1-deficient (SirT1[super]ko/ko) mice were generated by crossing a new strain of mice harboring a conditional targeted mutation in the SirT1 gene (SirT1[super]co/co) with CMV-Cre transgenic mice. Whole mount and histology analyses, immunofluorescence staining, immunohistochemistry, and western blotting were used to characterize mammary gland development in virgin and pregnant mice. The effect of exogenous estrogen was also examined by subcutaneous implantation of a slow-releasing pellet in the subscapular region. Results: Both male and female SirT1[super]ko/ko mice can be fertile despite the growth retardation phenotype. Virgin SirT1[super]ko/ko mice displayed impeded ductal morphogenesis, whereas pregnant SirT1[super]ko/ko mice manifested lactation failure due to an underdeveloped lobuloalveolar network. Estrogen implantation was sufficient to rescue ductal morphogenesis. Exogenous estrogen reversed the increased basal level of IGF-1 binding protein-1 expression in SirT1[super]ko/ko mammary tissues, but not that of I[kappa]B[alpha] expression, suggesting that increased levels of estrogen enhanced the production of local IGF-1 and rescued ductal morphogenesis. Additionally, TNF[alpha] treatment enhanced the level of the newly synthesized I[kappa]B[alpha] in SirT1[super]ko/ko cells. SirT1 deficiency therefore affects the cellular response to multiple extrinsic signals. Conclusion: SirT1 modulates the IGF-1 signaling critical for both growth regulation and mammary gland development in mice. SirT1 deficiency deregulates the expression of IGF-1 binding protein-1 and attenuates the effect of IGF-1 signals, including estrogen-stimulated local IGF-1 signaling for the onset of ductal morphogenesis. These findings suggest that the enzymatic activity of SirT1 may influence both normal growth and malignant growth of mammary epithelial cells. en_US
dc.description.sponsorship The study is supported by grants from the American Cancer Society (RSG-04-019-01-CNE) and the Nathan Shock Center of Excellence in the Biology of Aging at the University of Washington (to YG). en_US
dc.language.iso en_US en_US
dc.title SirT1 modulates the estrogen-insulin-like growth factor-1 signaling for postnatal development of mammary gland in mice en_US
dc.type Article en_US

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