Although the roles of progesterone and prolactin in mammary gland development have been extensively studied, the roles of Insulin, IGF1 and 1GF2 have received much less attention. The Neville laboratory recently found that a null mutation of the insulin receptor (IR) specifically in the secretory epithelium both impedes proliferative activity in eariy pregnancy and largely inhibits secretory differentiation in late pregnancy. We hypothesize that this receptor and one or more of its ligands are important modulators of mammary differentiation. Similariy, extensive work with the progesterone receptor (PR) in the mammary gland has shown that progesterone and PR are necessary for alveolar proliferation and development. There is also evidence that IR and PR work together to modulate each other's activity, although almost nothing is known about the mechanisms. In this project Dr. Neville and Dr. Edwards, an expert on PR, will work with two experts in metabolism, Drs. Carrie McCurdy and Paul MacLean, to investigate this new area. In vitro experiments will utilize unique 3D acinar cultures of mammary epithelial cells from virgin and 15 day pregnant mice to elucidate the molecular mechanisms by which these two regulatory pathways direct both proliferation and differentiation in the mammary gland. The investigators will also use mouse models of hypoinsulinemia and hyperinsulinemia to examine how conditions such as starvation, diabetes and obesity impinge on these pathways, and through them on milk secretion. Obesity, an increasingly common condition in most developing countries, is often associated with lactation failure in a population where breastfeeding is likely to be most beneficial to the infant. Understanding the mechanisms by which obesity alters mammary development and lactation competence may provide new therapeutic modalities that will enhance breastfeeding success.

Public Health Relevance

Obesity is a primary health concern worldwide that negatively impacts breastfeeding performance. Normally plasma insulin levels rise during pregnancy;preliminary data from our institution show that the rise is higher in obese women. Our studies offer a possible mechanistic link between the effects of insulin upon mammary development, lactation failure, and breast cancer development providing us with the basis for both diagnostic and potential therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD038129-14
Application #
8703142
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
City
Aurora
State
CO
Country
United States
Zip Code
80045
Treviño, Lindsey S; Bolt, Michael J; Grimm, Sandra L et al. (2016) Differential Regulation of Progesterone Receptor-Mediated Transcription by CDK2 and DNA-PK. Mol Endocrinol 30:158-72
Sladek, Celia D; Stevens, Wanida; Song, Zhilin et al. (2016) The ""metabolic sensor"" function of rat supraoptic oxytocin and vasopressin neurons is attenuated during lactation but not in diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 310:R337-45
Heinz, Richard E; Rudolph, Michael C; Ramanathan, Palani et al. (2016) Constitutive expression of microRNA-150 in mammary epithelium suppresses secretory activation and impairs de novo lipogenesis. Development 143:4236-4248
Rudolph, Michael C; Young, Bridget E; Jackson, Kristina Harris et al. (2016) Human Milk Fatty Acid Composition: Comparison of Novel Dried Milk Spot Versus Standard Liquid Extraction Methods. J Mammary Gland Biol Neoplasia 21:131-138
Wellberg, Elizabeth A; Rudolph, Michael C; Lewis, Andrew S et al. (2014) Modulation of tumor fatty acids, through overexpression or loss of thyroid hormone responsive protein spot 14 is associated with altered growth and metastasis. Breast Cancer Res 16:481
Schmidt, Jeffrey W; Wehde, Barbara L; Sakamoto, Kazuhito et al. (2014) Stat5 regulates the phosphatidylinositol 3-kinase/Akt1 pathway during mammary gland development and tumorigenesis. Mol Cell Biol 34:1363-77
Rudolph, Michael C; Wellberg, Elizabeth A; Lewis, Andrew S et al. (2014) Thyroid hormone responsive protein Spot14 enhances catalysis of fatty acid synthase in lactating mammary epithelium. J Lipid Res 55:1052-65
Pereira, Renata O; Wende, Adam R; Crum, Ashley et al. (2014) Maintaining PGC-1α expression following pressure overload-induced cardiac hypertrophy preserves angiogenesis but not contractile or mitochondrial function. FASEB J 28:3691-702
McManaman, James L (2014) Lipid transport in the lactating mammary gland. J Mammary Gland Biol Neoplasia 19:35-42
Wellberg, Elizabeth A; Anderson, Steven M (2014) FASNating targets of metformin in breast cancer stem-like cells. Horm Cancer 5:358-62

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