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.
Elizabeth Wellberg, Ph.D., Instructor
J.M., A. Calcabrini, L. Gonzalez , E. Martin-Forero, M.T. Agullo-Ortuno, V.
Simon, H. Watkin, S.M. Anderson, S. Roche, and J. Martin-Perez, 2010. ”A
noncatalytic function of Src family kinases in prolactin-induced Jak2
signaling.” Cell Signaling 22: 415-426.
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
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)
Yuan, Y. Wang, S.M. Anderson, and H. Gu, 2011 “Lactation defect in a widely
used MMTV-Cre transgenic line of mice.” PLOS One 6(4): e19233. PMID 21559430
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.
Young, A.S. Lewis, M.C. Rudolph, M.D. Ruehle, and S.M. Anderson, 2011.
“Modulation of glucose transporter 1 (GLUT1) expression levels alters mouse
mammary tumor cell growth in vitro and in vivo.” PLOS One 6(8): e2205. PMID
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. PMID 22728958.
Giles, E.A. Wellberg, D.P. Astling, S.M. Anderson, A.D. Thor, S. Jindal, A.C.
Tan, P.S. Schedin, and P.S. MacLean, 2012. “Obesity and overfeeding affecting
both tumor and systemic metabolism activates the progesterone receptor to
contribute to postmenopausal breast cancer.” Cancer Research 72 (24):
6490-6501. PMID 23222299.
Neville, P. Webb, P. Ramanathan, M. Phistry, C. Pecorini, J. Monks, S.M.
Anderson, P. MacLean, 2013. “The Insulin Receptor Plays an Important Role in
Secretory Differentiation in the Mammary Gland.” American Journal of Physiology-Endocrinology
and Metabolism 305 (9): E1103-1114. PMID: 23982156.
Wahdan-Alaswad, Z. Fan, S.M. Edgerton, B. Liu, X.-S. Deng, S. S. Arnadottir, J.
Richer, S.M. Anderson, and A.D. Thor, 2013. “Glucose Promotes Breast Cancer
Aggression and Reduces Metformin Efficacy.” Cell Cycle 12(24): 3759-3769. PMID:24107633.
Wie, T.S. Adwan, J. DeGregori, S.M. Anderson and M.E. Reyland, 2014. “Inhibiting tyrosine phosphorylation of PKC
delta protects the salivary gland from radiation damage.” Journal of Biological
Chemistry, EPub February 25, 2014
Rudolph, E.A. Wellberg, A.S. Lewis, A.L. Merz, N.K. Maluf, N.A. Serkova, and
S.M. Anderson, 2014. “Thyroid Hormone
Responsive Protein/Spot14 is a protein enhancer of fatty acid synthase
catalysis in mammary epithelium.” Journal of Lipid Research 55 (6): 1052-1065. EPub ahead of Print April 25, 2014. PMID 24771867.
Cochrane*, R. Wahdan-Alaswad*, N.S. Spoelstra, E.N. Howe, S.M. Anderson, A.D.
Thor and J.K. Richer, 2014. “Metformin-induced killing of triple negative
breast cancer cells is mediated by reduction in fatty acid synthase via
miRNA-193b.” Hormones and Cancer, Dec 5(6) 364-389. doi 10.1007/s12672-0188-8.
September 12 [Epub ahead of Print]. PMID 25213330.