Steve Anderson Professor Department of Pathology Molecular Biology Ph.D., The Rockefeller University, 1981 Campus Box 8104 Cancer Research Tower (RC1-South), Room 5121 Phone: 303-724-3742 steve.anderson@ucdenver.edu

My lab is interested in signaling pathways that regulate mammary gland development and tumorigenesis. We are interested in events that regulate secretory activation at parturition and have focused our efforts on two different signaling molecules: the nonreceptor tyrosine kinase Src and the serine/threonine protein kinase Akt. We have learned that Src plays an important role in ductal elongation in the mammary gland during puberty that appears to be mediated by stromal cells in addition to mammary epithelial cells. Src null mice also exhibit delayed or incomplete lactogenesis which results in death of pups. The production of milk proteins in cultures of primary mammary epithelial cells isolated from Src null ice is severely reduced implying that Src has a role in regulating the transcription and/or translation of milk proteins genes.

We have previously generated transgenic mice that express activated Akt1 in the mammary gland because expression of Akt1 increases late in pregnancy and remains high throughout lactation. These transgenic mice exhibit precocious lipid biosynthesis and expression of milk protein genes during pregnancy, impaired lactation, and delayed involution doe to suppression of apoptotic pathways in the mammary gland. Analysis of the myr-Akt1 transgenic mice in comparison to normal mice has provided new insights into the regulation of secretory activation. This has provided new models that allow us to determine how the fat content of diet is sensed with regard to the synthesis of milk fat.

We also have found that expression of activated Akt in the mammary gland accelerates tumorigenesis by the Erbb2/Neu oncogene shorting tumor latency from 210 days to 100-110 days. Expression of Akt in these mammary tumors enhances aerobic glycolysis (the Warburg Effect). ErbB2 is overexpressed or mutated in about one-third of all human breast cancer patients, and mutants that lead to the activation of Akt occur in the majority of all breast tumors, thus providing an important clinical tie for this research. We are currently investigating the mechanisms that underlie the changes in tumor metabolism specifically with regard to glucose metabolism and fatty acid biosynthesis.

Our interest in tumor metabolism has lead to collaborative studies in which we wish to examine the effect of obesity upon mammary tumorigenesis, and whether restoring glucose balance with anti-diabetic drugs can inhibit tumorigenesis or the growth of existing tumors.

Selected Publications

Buser, A.C., E. Handel-Gass, S.L. Wyszomeierski, W. Doppler, S.A. Leonhardt, J. Schaak, J.M. Rosen, H. Watkin, S.M. Anderson, and D.P. Edwards, 2007. Progesterone receptor repression of prolactin/Stat5-mediated transcription of the b-casein gene in mammary epithelial cells. Molecular Endocrinology 21:106-125.

M.C. Rudolph, J.L. McManaman, T. Phang, T. Russell, D.J. Kominsky, N.J. Serkove, S.M. Anderson, and M.C. Neville, 2007. “Metabolic regulation in the lactating mouse: A milk lipid synthesizing machine.” Physiological Genomics, 28: 323-336.

S.M. Anderson, M. Rudolph, J.L. McManaman, and M.C. Neville, 2007. ”Secretory activation: It’s not just about milk proteins synthesis!” 2007. Breast Cancer Research 9 (1): 204. Highly Accessed Publication.

T.R. Lyons, J. Thorburn, P.W. Ryan, A. Thorburn, S.M. Anderson, and C.K. Kassenbrock. “Regulation of the pro-apoptotic scaffolding protein POSH by Akt.” Journal of Biological Chemistry, 282: 21987-21997. Epub May 30, 2007.

M.C. Rudolph, M.C. Neville, and S.M. Anderson, 2007. ”Lipid synthesis in lactation: Diet and the fatty acid switch.” Journal of Mammary Gland Biology and Neoplasia, 12(4): 269-281.

Schwertfeger KL, Hunter S, Heasley LE, Leon RP, DeGregori J, and Anderson SM (2001) Prolactin stimulates activation of c- jun N-terminal kinase (JNK). Mol. Endocrinol., 15 :867-881.

Schwertfeger KL, Richert MM, and Anderson, SM (2001) Mammary gland involution is delayed by activated Akt in transgenic mice. Mol. Endocrinol. 15, 867-881.

Boonyaratanakornkit V, Scott MP, Ribon V, Sherman L, Anderson SM, Maller JL, Miller WT, and Edwards, DP (2001) Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases. Mol. Cell 8 :269-280.

Kassenbrock CK, Hunter S, Garl PM, Johnson GL, and Anderson SM, 2002. “Inhibition of Src family kinases blocks EGF-induced activation of Akt, phosphorylation of Cbl, and ubiquitination of the EGF receptor.” Journal of Biological Chemistry 277: 24967-24975.

Limesand, KH, Barzen KA, Quissell DO, and Anderson SM (2003) Synergistic suppression of apoptosis in salivary acinar cells by IGF1 and EGF: Role of Akt. Cell Death and Differentation, in press.

Sun W, Wei X, Kesavan K, Garrigton TP, Fan R, Mei J, Anderson SM, Gelfand EW, and Johnson GL (2003) MEKK2 and the adapter protein Lad regulate ERK5 activation by EGF via Src. Molecular and Cellular Biology, in press.

Latest Publications in PubMed