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

Li H, Rajendran GK, Liu N, Ware C, Rubin BP, Gu Y - Breast Cancer Res. (2007)

Bottom Line: The effect of exogenous estrogen was also examined by subcutaneous implantation of a slow-releasing pellet in the subscapular region.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Radiation Oncology, University of Washington School of Medicine, Seattle, WA 98195, USA.

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-kappaB, 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(ko/ko)) mice were generated by crossing a new strain of mice harboring a conditional targeted mutation in the SirT1 gene (SirT1(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(ko/ko) mice can be fertile despite the growth retardation phenotype. Virgin SirT1(ko/ko) mice displayed impeded ductal morphogenesis, whereas pregnant SirT1(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(ko/ko) mammary tissues, but not that of IkappaB alpha expression, suggesting that increased levels of estrogen enhanced the production of local IGF-1 and rescued ductal morphogenesis. Additionally, TNFalpha treatment enhanced the level of the newly synthesized IkappaB alpha in SirT1(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.

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SirT1 modulates estrogen–insulin-like growth factor-1 signaling for ductal morphogenesis: a model. (a) The insulin/insulin-like growth factor-1 (IGF-1) signaling system: both SirT1 and Akt kinases can negatively regulate the transcription activity of forkhead box 'other' protein (FoxO) proteins. SirT1 deficiency deregulates the expression of insulin-like growth factor-1 binding protein-1 (IGFBP-1), which may exert autocrine and/or paracrine effects to inhibit IGF-1. (b) Mammary epithelial precursor cells (EPC) express IGF-1 receptor (IGF-1R) and can differentiate into estrogen receptor (ER)-negative ductal epithelial cells (DEC-I) in response to maternal, circulating, or estrogen-stimulated, stromal cell (S)-derived local IGF-1. At the onset of puberty, ovarian estrogen, in synergy with growth hormone (GH), enhances the production of local IGF-1 and stimulates the differentiation of DEC-I to ER-positive ductal epithelial cells (DEC-II). SirT1 deficiency deregulates the expression of IGFBP-1 in adipose tissues (a), however, which attenuates the efficacy of the IGF-1 signaling and causes impeded ductal morphogenesis in virgin SirT1ko/ko mice. Either pregnancy or exogenous estrogen can overcome the impeded ductal morphogenesis in virgin SirT1ko/ko mice and can stimulate the differentiation of EPC.
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Figure 7: SirT1 modulates estrogen–insulin-like growth factor-1 signaling for ductal morphogenesis: a model. (a) The insulin/insulin-like growth factor-1 (IGF-1) signaling system: both SirT1 and Akt kinases can negatively regulate the transcription activity of forkhead box 'other' protein (FoxO) proteins. SirT1 deficiency deregulates the expression of insulin-like growth factor-1 binding protein-1 (IGFBP-1), which may exert autocrine and/or paracrine effects to inhibit IGF-1. (b) Mammary epithelial precursor cells (EPC) express IGF-1 receptor (IGF-1R) and can differentiate into estrogen receptor (ER)-negative ductal epithelial cells (DEC-I) in response to maternal, circulating, or estrogen-stimulated, stromal cell (S)-derived local IGF-1. At the onset of puberty, ovarian estrogen, in synergy with growth hormone (GH), enhances the production of local IGF-1 and stimulates the differentiation of DEC-I to ER-positive ductal epithelial cells (DEC-II). SirT1 deficiency deregulates the expression of IGFBP-1 in adipose tissues (a), however, which attenuates the efficacy of the IGF-1 signaling and causes impeded ductal morphogenesis in virgin SirT1ko/ko mice. Either pregnancy or exogenous estrogen can overcome the impeded ductal morphogenesis in virgin SirT1ko/ko mice and can stimulate the differentiation of EPC.

Mentions: SirT1 is an integral part of the IIS system that checks and balances the efficacy of insulin and IGF-1 signals. The IGF-1 signaling of the IIS system is required for survival after birth. As illustrated in Figure 7a, the function of SirT1 parallels the linear IGF-1/IGF-1 receptor/phosphoinositide-3'-OH kinase/Akt signaling pathway, both of which can negatively regulate the transcription activity of FoxOs. Mice harboring targeted mutations in either IGF-1 or the IGF-1 receptor gene exhibit perinatal lethality and growth retardation [44,45]. In the IGF-1 receptor-expressing cells, the binding of insulin and/or IGF-1 activates the phosphoinositide-3'-OH kinase and Akt kinase cascade for survival [8,9,13]. The phosphoinositide-3'-OH kinase/Akt signaling pathway is also highly conserved from worms to mammals, and functions to modulate energy metabolism and lifespan in lower organisms. The mammalian Akt kinase family has three members, Akt1–Akt3, which provide specificity and versatility. Mice lacking both the Akt1 and Akt2 genes display perinatal lethal and growth retardation phenotypes that are strikingly similar to that of either IGF-1 or IGF-1 receptor-deficient mice [46]. In this regard, SirT1ko/ko mice, as well as other strains of SirT1-deficienct mice, also exhibit perinatal lethal and growth retardation phenotypes (Figure 1c and Table 1) [22,23]. The consistent observation of perinatal lethal and growth retardation phenotypes from our study and studies with mice lacking IGF-1, the IGF-1 receptor, or Akt1/Akt2 suggests that upregulated FoxO activity unleashes the expression of downstream effector genes that lead to the birth-related stress. This birth-related stress may be related to the switch from a maternal level of IGF-1 to a neonatal level of IGF-1 because the surviving SirT1ko/ko mice can live into adulthood and can reproduce despite the growth retardation phenotype (Figure 1c). In this context, at least one of the FoxO-deficient mice strains, FoxO3 (Foxo3a/FKHRL1)-deficient mice, grow normally and develop functional mammary glands [47].


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

Li H, Rajendran GK, Liu N, Ware C, Rubin BP, Gu Y - Breast Cancer Res. (2007)

SirT1 modulates estrogen–insulin-like growth factor-1 signaling for ductal morphogenesis: a model. (a) The insulin/insulin-like growth factor-1 (IGF-1) signaling system: both SirT1 and Akt kinases can negatively regulate the transcription activity of forkhead box 'other' protein (FoxO) proteins. SirT1 deficiency deregulates the expression of insulin-like growth factor-1 binding protein-1 (IGFBP-1), which may exert autocrine and/or paracrine effects to inhibit IGF-1. (b) Mammary epithelial precursor cells (EPC) express IGF-1 receptor (IGF-1R) and can differentiate into estrogen receptor (ER)-negative ductal epithelial cells (DEC-I) in response to maternal, circulating, or estrogen-stimulated, stromal cell (S)-derived local IGF-1. At the onset of puberty, ovarian estrogen, in synergy with growth hormone (GH), enhances the production of local IGF-1 and stimulates the differentiation of DEC-I to ER-positive ductal epithelial cells (DEC-II). SirT1 deficiency deregulates the expression of IGFBP-1 in adipose tissues (a), however, which attenuates the efficacy of the IGF-1 signaling and causes impeded ductal morphogenesis in virgin SirT1ko/ko mice. Either pregnancy or exogenous estrogen can overcome the impeded ductal morphogenesis in virgin SirT1ko/ko mice and can stimulate the differentiation of EPC.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1851382&req=5

Figure 7: SirT1 modulates estrogen–insulin-like growth factor-1 signaling for ductal morphogenesis: a model. (a) The insulin/insulin-like growth factor-1 (IGF-1) signaling system: both SirT1 and Akt kinases can negatively regulate the transcription activity of forkhead box 'other' protein (FoxO) proteins. SirT1 deficiency deregulates the expression of insulin-like growth factor-1 binding protein-1 (IGFBP-1), which may exert autocrine and/or paracrine effects to inhibit IGF-1. (b) Mammary epithelial precursor cells (EPC) express IGF-1 receptor (IGF-1R) and can differentiate into estrogen receptor (ER)-negative ductal epithelial cells (DEC-I) in response to maternal, circulating, or estrogen-stimulated, stromal cell (S)-derived local IGF-1. At the onset of puberty, ovarian estrogen, in synergy with growth hormone (GH), enhances the production of local IGF-1 and stimulates the differentiation of DEC-I to ER-positive ductal epithelial cells (DEC-II). SirT1 deficiency deregulates the expression of IGFBP-1 in adipose tissues (a), however, which attenuates the efficacy of the IGF-1 signaling and causes impeded ductal morphogenesis in virgin SirT1ko/ko mice. Either pregnancy or exogenous estrogen can overcome the impeded ductal morphogenesis in virgin SirT1ko/ko mice and can stimulate the differentiation of EPC.
Mentions: SirT1 is an integral part of the IIS system that checks and balances the efficacy of insulin and IGF-1 signals. The IGF-1 signaling of the IIS system is required for survival after birth. As illustrated in Figure 7a, the function of SirT1 parallels the linear IGF-1/IGF-1 receptor/phosphoinositide-3'-OH kinase/Akt signaling pathway, both of which can negatively regulate the transcription activity of FoxOs. Mice harboring targeted mutations in either IGF-1 or the IGF-1 receptor gene exhibit perinatal lethality and growth retardation [44,45]. In the IGF-1 receptor-expressing cells, the binding of insulin and/or IGF-1 activates the phosphoinositide-3'-OH kinase and Akt kinase cascade for survival [8,9,13]. The phosphoinositide-3'-OH kinase/Akt signaling pathway is also highly conserved from worms to mammals, and functions to modulate energy metabolism and lifespan in lower organisms. The mammalian Akt kinase family has three members, Akt1–Akt3, which provide specificity and versatility. Mice lacking both the Akt1 and Akt2 genes display perinatal lethal and growth retardation phenotypes that are strikingly similar to that of either IGF-1 or IGF-1 receptor-deficient mice [46]. In this regard, SirT1ko/ko mice, as well as other strains of SirT1-deficienct mice, also exhibit perinatal lethal and growth retardation phenotypes (Figure 1c and Table 1) [22,23]. The consistent observation of perinatal lethal and growth retardation phenotypes from our study and studies with mice lacking IGF-1, the IGF-1 receptor, or Akt1/Akt2 suggests that upregulated FoxO activity unleashes the expression of downstream effector genes that lead to the birth-related stress. This birth-related stress may be related to the switch from a maternal level of IGF-1 to a neonatal level of IGF-1 because the surviving SirT1ko/ko mice can live into adulthood and can reproduce despite the growth retardation phenotype (Figure 1c). In this context, at least one of the FoxO-deficient mice strains, FoxO3 (Foxo3a/FKHRL1)-deficient mice, grow normally and develop functional mammary glands [47].

Bottom Line: The effect of exogenous estrogen was also examined by subcutaneous implantation of a slow-releasing pellet in the subscapular region.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Radiation Oncology, University of Washington School of Medicine, Seattle, WA 98195, USA.

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-kappaB, 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(ko/ko)) mice were generated by crossing a new strain of mice harboring a conditional targeted mutation in the SirT1 gene (SirT1(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(ko/ko) mice can be fertile despite the growth retardation phenotype. Virgin SirT1(ko/ko) mice displayed impeded ductal morphogenesis, whereas pregnant SirT1(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(ko/ko) mammary tissues, but not that of IkappaB alpha expression, suggesting that increased levels of estrogen enhanced the production of local IGF-1 and rescued ductal morphogenesis. Additionally, TNFalpha treatment enhanced the level of the newly synthesized IkappaB alpha in SirT1(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.

Show MeSH
Related in: MedlinePlus