Expression of constitutively activated Akt in the mammary gland leads to excess lipid synthesis during pregnancy and lactation

Schwertfeger, Kathryn L.; McManaman, James L.; Palmer, Carol A.; Neville, Margaret C.; Anderson, Steven M.

doi:10.1194/jlr.m300045-jlr200

Cited by 127 publications

(120 citation statements)

References 68 publications

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“…Interestingly, recent studies have shown that OSBPs can inhibit the catalytic activity of PP2A phosphatases that are involved in the control of the phosphorylation of Akt (34). Akt has been reported to control lipid metabolism during lactation in mice (35,36), and okadaic acid, an inhibitor of PP2A, stimulates the differentiation of breast cancer cells (37). This suggests that oxysterols can control lactation processes in normal breast and in breast cancer cells through OSBP-related proteins by inhibiting the dephosphorylation of Akt.…”

Section: Discussionmentioning

confidence: 99%

Microsomal antiestrogen-binding site ligands induce growth control and differentiation of human breast cancer cells through the modulation of cholesterol metabolism

Payré

Médina

Boubekeur

et al. 2008

Molecular Cancer Therapeutics

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The microsomal antiestrogen-binding site (AEBS) is a highaffinity membranous binding site for the antitumor drug tamoxifen that selectively binds diphenylmethane derivatives of tamoxifen such as PBPE and mediates their antiproliferative properties. The AEBS is a hetero-oligomeric complex consisting of 3B-hydroxysterol-# 8 -# 7 -isomerase and 3B-hydroxysterol-# 7 -reductase. High-affinity AEBS ligands inhibit these enzymes leading to the massive intracellular accumulation of zymostenol or 7-dehydrocholesterol (DHC), thus linking AEBS binding to the modulation of cholesterol metabolism and growth control. The aim of the present study was to gain more insight into the control of breast cancer cell growth by AEBS ligands. We report that PBPE and tamoxifen treatment induced differentiation in human breast adenocarcinoma cells MCF-7 as indicated by the arrest of cells in the G 0 -G 1 phase of the cell cycle, the increase in the cell volume, the accumulation and secretion of lipids, and a milk fat globule protein found in milk. These effects were observed with other AEBS ligands and with zymostenol and DHC. Vitamin E abrogates the induction of differentiation and reverses the control of cell growth produced by AEBS ligands, zymostenol, and DHC, showing the importance of the oxidative processes in this effect. AEBS ligands induced differentiation in estrogen receptor-negative mammary tumor cell lines SKBr-3 and MDA-MB-468 but with a lower efficiency than observed with MCF-7. Together, these data show that AEBS ligands exert an antiproliferative effect on mammary cancer cells by inducing cell differentiation and growth arrest and highlight the importance of cholesterol metabolism in these effects.

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Section: Discussionmentioning

confidence: 99%

Microsomal antiestrogen-binding site ligands induce growth control and differentiation of human breast cancer cells through the modulation of cholesterol metabolism

Payré

Médina

Boubekeur

et al. 2008

Molecular Cancer Therapeutics

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“…Thus, a reasonable hypothesis is that key mediators of insulin signaling might be necessary to establish or maintain a normal lactation. To date, there have been only limited attempts at establishing the functional importance of specific insulin signaling molecules to the process of lactogenesis (Li et al 2002, Schwertfeger et al 2003. Our studies make several novel observations concerning the importance of IRS proteins to lactation.…”

Section: Discussionmentioning

confidence: 55%

“…The immunoblot results in the current study extend that observation by demonstrating that this upregulation of IRS-1 and IRS-2 is an early event that is temporally linked with the process of secretory activation. The published results on other components of the insulin signaling pathway have also demonstrated increased expression of both the insulin receptor and Akt with the onset of lactation, suggesting that the coordinated upregulation of multiple insulin signaling pathway components may occur during the early post partum period (Flint 1982, Schwertfeger et al 2003.…”

Section: Discussionmentioning

confidence: 99%

“…The activation of Akt in response to insulin or IGF-I stimulation mediates the ability of these two hormones to inhibit apoptosis (Datta et al 1997). However, activation of Akt has also been demonstrated to mediate the effects of insulin on protein synthesis, carbohydrate metabolism, and lipid biosynthesis (Mendez et al 1996, Gottlob et al 2001, Schwertfeger et al 2003.…”

Section: Introductionmentioning

confidence: 99%

“…Lactogenesis I is characterized by the detectable induction of lactation-specific gene products within the mammary epithelium. In rodents, this process begins as early as day 10 of pregnancy and is associated with a variety of biochemical as well as morphological changes within the mammary epithelium (Bauman et al 1974, Mellenberger & Bauman 1974b, Slaby & Brown 1974, Rosen & Barker 1976, Nakhasi & Qasba 1979, Schwertfeger et al 2003. Lactogenesis II, also referred to as secretory activation, is characterized by a switch that occurs within the secretory epithelium from the pre-lactating differentiated state described earlier, to a state of intense metabolic, biosynthetic, and secretory activity.…”

Section: Introductionmentioning

confidence: 99%

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Decreased lactation capacity and altered milk composition in insulin receptor substrate null mice is associated with decreased maternal body mass and reduced insulin-dependent phosphorylation of mammary Akt

Hadsell

Olea²,

Lawrence³

et al. 2007

Journal of Endocrinology

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Expression of insulin receptor substrates (IRS)-1 and -2 within the mammary gland was found to be high at midlactation and dramatically decreased with mammary involution. This observation supports the hypothesis that these proteins are induced in the mammary gland with lactogenesis and involved in normal milk synthesis. To test this hypothesis, lactation capacity, along with indices of mammary secretory cell glucose metabolism and cell signaling were compared in normal mice and mice carrying targeted mutations in either the Irs1 or Irs2 genes. Mammary IRS-1 and IRS-2 protein levels were increased within 1 day of parturition and reached maximal levels by 5 days post partum. Dams carrying germline mutations of Irs1 or Irs2 displayed reduced lactation capacity as assessed by weight gain of pup litters. The reduction was more dramatic in Irs1 K/K versus Irs2 K/K dams. Maternal body weight was also reduced in Irs1 K/K dams as well as in Irs1 Irs2C/K dams. The loss of IRS-1 had little impact on mammary gland expression of milk protein mRNAs, glucose transport, or on the abundance and subcellular localization of hexokinases I and II. The loss of IRS-1 was associated with a compensatory increase in insulin-induced IRS-2 phosphorylation; however, the loss of IRS-1 did also cause a reduction in insulin-dependent mammary gland-specific activation of Akt phosphorylation. These results support the conclusion that IRS-1 is important for insulin-dependent activation of Akt signaling within the lactating mammary gland, but that loss of this protein has only modest impact on normal milk synthesis, since related signaling proteins such as IRS-2 may act in compensatory fashion.

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Biology of insulin‐like growth factors in development

Dupont¹,

Holzenberger²

2003

Birth Defects Research Pt C

177

140

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Insulin-like growth factors (IGFs) provide essential signals for the control of embryonic and postnatal development in vertebrate species. In mammals, IGFs act through and are regulated by a system of receptors, binding proteins, and related proteases. In each of the many tissues dependent on this family of growth factors, this system generates a complex interaction specific to the tissue concerned. Studies carried out over the last decade, mostly with transgenic and gene knockout mouse models, have demonstrated considerable variety in the cell type-specific and developmental stage-specific functions of IGF signals. Brain, muscle, bone, cartilage, pancreas, ovary, skin, and fat tissue have been identified as major in vivo targets for IGFs. Concentrating on several of these organ systems, we review here phenotypic analyses of mice with genetically modified IGF systems. Much progress has also been made in understanding the specific intracellular signaling cascades initiated by the binding of circulating IGFs to their cognate receptor. We also summarize the most relevant aspects of this research. Considerable efforts are currently focused on deciphering the functional specificities of intracellular pathways, particularly the molecular mechanisms by which cells distinguish growth-stimulating insulin-like signals from metabolic insulin signals. Finally, there is a growing body of evidence implicating IGF signaling in lifespan control, and it has recently been shown that this function has been conserved throughout evolution. Very rapid progress in this domain seems to indicate that longevity may be subject to IGF-dependent neuroendocrine regulation and that certain periods of the life cycle may be particularly important in the determination of individual lifespan.

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Expression of constitutively activated Akt in the mammary gland leads to excess lipid synthesis during pregnancy and lactation

Cited by 127 publications

References 68 publications

Microsomal antiestrogen-binding site ligands induce growth control and differentiation of human breast cancer cells through the modulation of cholesterol metabolism

Microsomal antiestrogen-binding site ligands induce growth control and differentiation of human breast cancer cells through the modulation of cholesterol metabolism

Decreased lactation capacity and altered milk composition in insulin receptor substrate null mice is associated with decreased maternal body mass and reduced insulin-dependent phosphorylation of mammary Akt

Biology of insulin‐like growth factors in development

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