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Key stages in mammary gland development. Secretory activation in the mammary gland: it's not just about milk protein synthesis!

Anderson SM, Rudolph MC, McManaman JL, Neville MC - Breast Cancer Res. (2007)

Bottom Line: Much of the research to date on mammary epithelial differentiation has focused upon expression of milk protein genes, providing a somewhat distorted view of alveolar differentiation and secretory activation.While expression of milk protein genes increases during pregnancy and at secretory activation, the genes whose expression is more tightly regulated at this transition are those that regulate lipid biosynthesis.The sterol regulatory element binding protein (SREBP) family of transcription factors is recognized as regulating fatty acid and cholesterol biosynthesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, University of Colorado Health Sciences Center, East 17th Avenue, Aurora, CO 80045, USA. Steve.Anderson@uchsc.edu

ABSTRACT
The transition from pregnancy to lactation is a critical event in the survival of the newborn since all the nutrient requirements of the infant are provided by milk. While milk contains numerous components, including proteins, that aid in maintaining the health of the infant, lactose and milk fat represent the critical energy providing elements of milk. Much of the research to date on mammary epithelial differentiation has focused upon expression of milk protein genes, providing a somewhat distorted view of alveolar differentiation and secretory activation. While expression of milk protein genes increases during pregnancy and at secretory activation, the genes whose expression is more tightly regulated at this transition are those that regulate lipid biosynthesis. The sterol regulatory element binding protein (SREBP) family of transcription factors is recognized as regulating fatty acid and cholesterol biosynthesis. We propose that SREBP1 is a critical regulator of secretory activation with regard to lipid biosynthesis, in a manner that responds to diet, and that the serine/threonine protein kinase Akt influences this process, resulting in a highly efficient lipid synthetic organ that is able to support the nutritional needs of the newborn.

Show MeSH
Expression of regulatory genes during secretory differentiation and activation. Dotted lines show genes that decrease at least ten-fold during pregnancy, consistent with adipocyte localization. The solid lines show genes that increase at least two-fold at the onset of lactation with much smaller changes during pregnancy. These genes are likely to be important in initiating metabolic changes at secretory activation. LXR, liver X receptor; P17, day 17 of pregnancy; PPAR, proliferator-activated receptor; PrlR, prolactin receptor; SREBP, sterol regulatory element binding protein.
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Figure 7: Expression of regulatory genes during secretory differentiation and activation. Dotted lines show genes that decrease at least ten-fold during pregnancy, consistent with adipocyte localization. The solid lines show genes that increase at least two-fold at the onset of lactation with much smaller changes during pregnancy. These genes are likely to be important in initiating metabolic changes at secretory activation. LXR, liver X receptor; P17, day 17 of pregnancy; PPAR, proliferator-activated receptor; PrlR, prolactin receptor; SREBP, sterol regulatory element binding protein.

Mentions: Figure 7 shows the expression of a number of genes known to be involved in the regulation of lipid synthesis in liver, adipose tissue and the mammary gland. Two expression patterns emerge. Several factors, shown by the dotted lines in Figure 7, are downregulated up to ten-fold or more during pregnancy, consistent with the pattern of expression of adipocyte genes shown in Figure 3. These include Akt2, peroxisome-proliferator-activated receptor-gamma (PPAR-γ), and liver X receptor-beta (LXR-β), all known to be involved in regulation of lipid synthesis in adipose tissue. On the other hand, Akt1, the long form of the PRLR, SREBP1, and a protein thought to be important in the regulation of fatty acid synthesis, SPOT 14 [89], are all significantly upregulated between day 17 of pregnancy and day 2 of lactation. We have shown that Akt1 is dramatically upregulated at both the mRNA and protein levels during lactation [25,90] and have previously described the lactation failure that occurs in transgenic mice expressing constitutively activated myr-Akt1 in the mammary gland [25]. CLD formation occurs during early pregnancy in these mice, and they produce milk with an elevated lipid content (25% to 30% in normal FVB mice versus 65% to 70% in the transgenic mice by creamatocrit, a volume/volume method) [25]. Microarray studies comparing myr-Akt1 transgenic mice to FVB control mice indicate that expression of several key regulatory fatty acid biosynthetic enzymes is elevated during pregnancy in these transgenic mice, including SREBP1, Insig1, and Spot 14 (MC Rudolph, MC Neville, and SM Anderson, unpublished data).


Key stages in mammary gland development. Secretory activation in the mammary gland: it's not just about milk protein synthesis!

Anderson SM, Rudolph MC, McManaman JL, Neville MC - Breast Cancer Res. (2007)

Expression of regulatory genes during secretory differentiation and activation. Dotted lines show genes that decrease at least ten-fold during pregnancy, consistent with adipocyte localization. The solid lines show genes that increase at least two-fold at the onset of lactation with much smaller changes during pregnancy. These genes are likely to be important in initiating metabolic changes at secretory activation. LXR, liver X receptor; P17, day 17 of pregnancy; PPAR, proliferator-activated receptor; PrlR, prolactin receptor; SREBP, sterol regulatory element binding protein.
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Related In: Results  -  Collection

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Figure 7: Expression of regulatory genes during secretory differentiation and activation. Dotted lines show genes that decrease at least ten-fold during pregnancy, consistent with adipocyte localization. The solid lines show genes that increase at least two-fold at the onset of lactation with much smaller changes during pregnancy. These genes are likely to be important in initiating metabolic changes at secretory activation. LXR, liver X receptor; P17, day 17 of pregnancy; PPAR, proliferator-activated receptor; PrlR, prolactin receptor; SREBP, sterol regulatory element binding protein.
Mentions: Figure 7 shows the expression of a number of genes known to be involved in the regulation of lipid synthesis in liver, adipose tissue and the mammary gland. Two expression patterns emerge. Several factors, shown by the dotted lines in Figure 7, are downregulated up to ten-fold or more during pregnancy, consistent with the pattern of expression of adipocyte genes shown in Figure 3. These include Akt2, peroxisome-proliferator-activated receptor-gamma (PPAR-γ), and liver X receptor-beta (LXR-β), all known to be involved in regulation of lipid synthesis in adipose tissue. On the other hand, Akt1, the long form of the PRLR, SREBP1, and a protein thought to be important in the regulation of fatty acid synthesis, SPOT 14 [89], are all significantly upregulated between day 17 of pregnancy and day 2 of lactation. We have shown that Akt1 is dramatically upregulated at both the mRNA and protein levels during lactation [25,90] and have previously described the lactation failure that occurs in transgenic mice expressing constitutively activated myr-Akt1 in the mammary gland [25]. CLD formation occurs during early pregnancy in these mice, and they produce milk with an elevated lipid content (25% to 30% in normal FVB mice versus 65% to 70% in the transgenic mice by creamatocrit, a volume/volume method) [25]. Microarray studies comparing myr-Akt1 transgenic mice to FVB control mice indicate that expression of several key regulatory fatty acid biosynthetic enzymes is elevated during pregnancy in these transgenic mice, including SREBP1, Insig1, and Spot 14 (MC Rudolph, MC Neville, and SM Anderson, unpublished data).

Bottom Line: Much of the research to date on mammary epithelial differentiation has focused upon expression of milk protein genes, providing a somewhat distorted view of alveolar differentiation and secretory activation.While expression of milk protein genes increases during pregnancy and at secretory activation, the genes whose expression is more tightly regulated at this transition are those that regulate lipid biosynthesis.The sterol regulatory element binding protein (SREBP) family of transcription factors is recognized as regulating fatty acid and cholesterol biosynthesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, University of Colorado Health Sciences Center, East 17th Avenue, Aurora, CO 80045, USA. Steve.Anderson@uchsc.edu

ABSTRACT
The transition from pregnancy to lactation is a critical event in the survival of the newborn since all the nutrient requirements of the infant are provided by milk. While milk contains numerous components, including proteins, that aid in maintaining the health of the infant, lactose and milk fat represent the critical energy providing elements of milk. Much of the research to date on mammary epithelial differentiation has focused upon expression of milk protein genes, providing a somewhat distorted view of alveolar differentiation and secretory activation. While expression of milk protein genes increases during pregnancy and at secretory activation, the genes whose expression is more tightly regulated at this transition are those that regulate lipid biosynthesis. The sterol regulatory element binding protein (SREBP) family of transcription factors is recognized as regulating fatty acid and cholesterol biosynthesis. We propose that SREBP1 is a critical regulator of secretory activation with regard to lipid biosynthesis, in a manner that responds to diet, and that the serine/threonine protein kinase Akt influences this process, resulting in a highly efficient lipid synthetic organ that is able to support the nutritional needs of the newborn.

Show MeSH