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 SirT1^ko/ko mice. Either pregnancy or exogenous estrogen can overcome the impeded ductal morphogenesis in virgin SirT1^ko/ko mice and can stimulate the differentiation of EPC.