Every year approximately 200,000 new cases of breast cancer are diagnosed, and 40,000 women are expected to die from this disease in the U.S. alone. Our labs long-term goal is to identify novel therapeutic targets for treatment of breast cancer. We are trying to understand alterations in cellular signaling pathways between normal and cancer cells and exploit these differences for possible therapeutic gain.
Our lab has two major areas of interest:
1. We are trying to understand how cancer cells survive in the absence of cell adhesion. Normal epithelial cells readily undergo cell death in the absence of matrix signals (referred to as anoikis). Cancer cells, and oncogenes such as tyrosine kinase family of receptors, provide survival signals that allow anoikis resistance and enable cancer cell to survive in inappropriate environments and spread. Our lab has found a critical interplay between specific adhesion receptors (integrins) with the EGF receptor family of tyrosine kinase receptors in regulating anoikis. In addition, in collaboration with Dr. Gregg Johannes (Dept. of Pathology), we are examining how low oxygen levels (hypoxia) regulate signaling pathways associated with cancer phenotypes using standard and three-dimmensional epithelial culture assays.
2. Recently, our lab has become interested in understanding how metabolic reprogramming in cancer cell alter signaling regulating oncogenic pathways. Tumor cells take up ten times more glucose then normal cells and switch to glycolysis to meet energy needs. In collaboration with Dr. Keith Vosseller (Dept. of Biochem. & Mol. Biology), we have found that a nutrient-sensing pathway that regulates sugar-based protein modification, called O-GlcNAcylation, is highly elevated in breast and prostate cancers. Reducing O-GlcNAcylation in cancer cells inhibits growth, invasion and metastasis. Thus targeting the enzyme that regulates O-GlcNAcylation, O-GlcNAc transferase, may provide novel way of to treat cancers. We are currently investigating how O-GlcNAcylation regulates oncogenic signaling pathways using in vitro and in vivo cancer models.
Selected Publications
"Critical role of O-GlcNAc transferase in prostate cancer invasion, angiogenesis, and metastasis"
Lynch, TP, Ferrer, C, Jackson, SR, Shahriari, KS, Vosseller, K, and Reginato, MJ
Submitted (2011).
"K-Ras activation of ERK2 in a three-dimensional model of human pancreatic cells regulates invasion via induction of matrix metalloproteinase-1"
Botta, GP, Reginato, MJ, Rustgi, AK, and Lelkes, PI
Submitted (2011).
"Surviving without oxygen: Hypoxia regulation of mammary morphogenesis and anoikis"
Whelan, KA and Reginato, MJ
Cell Cycle Jul 15: 10, 2287-94 (2011).
"Cellular FLIP(L) plays a survival role and regulates morphogenesis in breast epithelial cells"
Yerbes, R, Palacios, C, Reginato, MJ, and Lopez-Rivas, A
Biochim Biophys Acta Jan: 1813, 168-78 (2011).
"O-GlcNAc transferase: A sweet new cancer target"
Lynch, TP and Reginato, MJ
Cell Cycle June 1: 10, 1712-13 (2011).
"Hypoxia suppression of Bim and Bmf blocks anoikis and luminal clearing during mammary morphogenesis"
Whelan, KA, Caldwell, SA, Shahriari, KS, Jackson, SR, Jones, L, Johannes, G and Reginato, MJ
Mol. Biol. Cell. Nov 15: 21, 3829-37 (2010).
"Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis via targeting of the oncogenic transcription factor FoxM1"
Caldwell, SA, Jackson, SR, Shahriari, KS, Lynch, TP, Sethi, G, Walker, S, Vosseller, K, and Reginato, MJ
Oncogene May 13: 29, 2831-42 (2010).
"ErbB2 requires integrin alpha5 for anoikis resistance via c-Src regulation of receptor activity in human mammary epithelial cells"
Haenssen, KK, Caldwell, SA, Shahriari, K, Jackson, R, Whelan, K, Klein-Szanto, A, and Reginato, MJ
J. of Cell Science April 15: 123, 1373-82 (2010).
"Micropatterns of matrigel for three-dimensional epithelial cultures"
Sodunke, TR, Turner, KK, Caldwell, SA, McBride, KW, Reginato, MJ and Noh, N
Biomaterials 28, 4006-16 (2007).
"Illuminating the center: mechanisms regulating lumen formation and maintenance in mammary morphogenesis"
Reginato, MJ, and Muthuswamy, SK
J Mammary Gland Biology & Neoplasia 11, 205-11 (2006)
"Bim regulation of lumen formation in cultured mammary epithelial acini is targeted by oncogenes"
Reginato, MJ, Mills, KR, Becker, EB, Lynch, DK, Bonni, A, Muthuswamy S, and Brugge, JS
Mol. Cell. Biol. 25, 4591-4601 (2005).
"Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis"
Reginato, MJ, Mills, KR, Paulus, JK, Lynch, DK, Sgroi, DC, Debnath J, Muthuswamy S, and Brugge, JS
Nature Cell Biology 5, 733-740 (2003).
"The role of apoptosis in creating and maintaining luminal space within normal and oncogene expressing mammary acini"
Debnath, J, Mills, KR, Collins, N, Reginato, MJ, Muthuswamy S, and Brugge, JS
Cell 111, 29-40 (2002).
All publications
News:
Study links cancer growth to sugar-based modification found naturally in the body
|