Vice Chair for Research
James C. Todd Professor of Experimental Pathology
Phone: (303) 724-3742
Fax: (303) 724-3712
My lab is interested in signaling pathways that regulate mammary gland development and tumorigenesis. Our interest in mammary gland development has been stimulated by our studies of the MMTV-myr-Akt1 transgenic mice in which we observed that expression of activated Akt1 stimulated the precocious appearance of cytoplasmic lipid droplets during pregnancy. This stimulated us to examine the molecular switches in mice that regulate lipid biosynthesis at secretory activation, the transition from pregnancy to lactation. The major source of calories in mouse milk is present in the fat component, which is important for development of the nervous system as well as normal growth. The magnitude of the contribution of the fat present in mouse milk is revealed by the fact that an average mouse will secrete her entire body weight in milk fat. This fat is either derived from dietary fat, or is synthesized de novo from glucose. We are using genetically modified mice to examine the roles of various signaling molecules and transcription factors in regulating lipid biosynthesis in the lactating mammary gland. We have also learned that Akt is important in regulating involution of the mammary gland.
Crossing transgenic mice that express activated Akt (MMTV-myr-Akt1 transgenic mice) to MMTV-ErbB2 transgenic mice accelerates mammary tumorigenesis. MMTV-c-ErbB2 transgenic mice typically develop mammary tumors in 230 days; however bitransgenic mice expressing both c-ErbB2 and myr-Akt1 develop tumors in about 1110 days. We continue to characterize the molecular changes that underlie the accelerated tumorigenesis in these mice.Tumor cells are known to display an altered metabolism that is characterized by increased glucose uptake, an increase in glycolysis, and the increased secretion of lactate, a waste product of glycolysis. We have been examining the effect of altering the expression of the hexose transporter GLUT1 upon tumorigenesis in vivo. Inhibiting expression of GLUT1 decreases the initial growth of tumors in vivo, while overexpressing GLUT1 enhances tumor growth. We continue to probe the role of glucose in tumor metabolism and how modifying glucose flux may alter tumor growth. Since glucose is also critical in the lactating mammary gland, there may be important links between the metabolism of tumor cells and mammary epithelial cells during lactation.
Finally, in collaboration with Drs. MacLean, Schedin, and Thor, we are investigating the effects of obesity upon mammary tumorigenesis and whether restoring glucose balance and insulin sensitivity has an impact upon tumor growth in vivo. Since obesity is approaching epidemic proportions in our country, these studies have important clinical implications for the prevention and treatment of breast cancer.
Michael Rudolph, Molecular Biology
Elizabeth Wellberg, Ph.D., Post-doctoral Fellow
1 C.D. Young and S.M. Anderson, 2008. “Sugar and fat-that’s where it is at: metabolic changes in tumors.” Breast Cancer Research, 10(1): 202. PMID 18304378
2. C.D. Young, E. Nolte, A. Lewis, N. Serkova, and S.M. Anderson, 2008. “Activated Akt1 accelerates mammary tumorigenesis in the MMTV-c-ErbB2 transgenic mice without activation of ErbB3.” Breast Cancer Research, 10 (4): R70. PMID 18700973
3. C.D. Young and S.M. Anderson, 2009. “Rah, rah, ROS: metabolic changes caused by loss of adhesion induce cell death.” Breast Cancer Research 11:307. PMID 19930622
4. M.C. Rudolph, E.A. Wellberg, and S.M. Anderson, 2009. “Adipose depleted mammary epithelial organoid cells.” J. Mammary Gland Biology and Neoplasia 14: 381-386. PMID 19963686
5. A.C. Nelson, T.R. Lyons, K.C. Hansen, L.A. Kiemele, C.D. Young, S.M. Anderson, and J.T. Holt, 2010. “AKT regulates BRCA1 stability in response to estrogen signaling.” Molecular and Cellular Endocrinology 319 (1-2): 129-142. PMID 20085797
6. B.L. Allen-Petersen, M.R. Miller, M.C. Neville, S.M. Anderson, K.I. Nakayama, and M.E. Reyland, 2010. “Loss of protein kinase C delta alters mammary gland development and apoptosis.” Cell Death and Disease. 1. e17 (21 January 2010) doi:10.1038/cddis.2009.20 PMID 21364618
7. M.C. Rudolph, J. Monks, V. Burns, M. Phistry, R. Marians, M.R. Foote, D.E. Bauman, S.M. Anderson*, and M.C Neville*, 2010. “Sterol regulatory element binding protein (SREBPF-1) and dietary lipid regulation of fatty acid synthesis in the mammary epithelium.” American Journal of Physiology-Endocrinology and Metabolism 299(6): E918-927. PMID 20739508 (*denotes Co-senior authors)
8. M.C. Rudolph, T.D. Russell, M.C. Neville, and S.M. Anderson, 2011. “Prolactin-mediated regulation of lipid biosynthesis genes in vivo in the lactating mammary epithelial cell.” American Journal of Physiology-Endocrinology and Metabolism 300 (6) E1059-1068. PMID 21467304.
9. C.D. Young, A.S. Lewis, M.C. Rudolph, M.D. Ruehle, and S.M. Anderson, 2011. “Glut1 is required for efficient tumor growth by mouse mammary carcinoma cells.” PLOS One 6(8): e2205. PMID 21826239.
10. M.C. Neville, S.M. Anderson, J.L. McManaman, T. M. Badger, M. Bunik, N. Contractor, T. Crume, D. Dabelea, S.M. Donovan, N. Forman, D.N. Frank, J.E. Friedman, J.B. German, A. Goldman, D. Hadsell, M. Hambidge, K. Hinde, N.D. Horseman, R.C. Hovey, E. Janoff, N. Krebs, C.B. Lebrilla5, D.G. Lemay, P.S. MacLean, P. Meier, A. Morrow, J. Neu, L.A. Nommsen-Rivers, M. Rijnkels, V. Seewaldt, B.D. Shur, J. VanHouten, P. Williamson, 2012. “Lactation and Neonatal Nutrition: Defining and Refining the Critical Questions,” J. Mammary Gland Biology and Neoplasia 17 (2): 167-188. PMID 22752723.
11. Rudolph, M.C., N.K. Maluf, E.A. Wellberg, C.A. Johnson, R.C. Murphy, and S.M. Anderson, 2012. “Mammalian fatty acid synthase activity from crude lysates tracing (13)C-labelled substrates using gas chromatography-mass spectrometry.” Anal. Biochem. 428 (15): 158-166. June 20, 2012. Epub ahead of print. PMID 22728958.