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 lab's 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 oncogenes regulate cancer cell signaling and progression to more aggressive phenotypes using standard and three-dimensional (3D) culture assays. In 3D culture, normal cells form polarized, hollow duct-like structures that resemble mammary ducts in vivo. Cancer cells, and oncogenes such as tyrosine kinase family of receptors, including HER2/ErbB2, provide signals that allow disruption of morphogenesis including increase in cell growth and inhibition of cell death pathways. However, these structures remain surrounded by intact basement membrane and are considered to have properties of pre-cancers. Our lab is very interested in understanding signals that drive cells from pre-cancer to malignant state. Cells expressing constitutively active form of ErbB2, or very aggressive breast cancer cells, are able to invade through the matrix and have properties of malignant cells. In addition, in collaboration with Dr. Gregg Johannes (Department of Pathology), we are examining how low oxygen levels (hypoxia) regulate signaling pathways associated with cancer progression and chemoresistance.
2. Our lab is also interested in understanding how oncogenes alter metabolic reprogramming in cancer cells. Tumor cells take up ten times more glucose than normal cells and switch to glycolysis to meet energy needs. In collaboration with Dr. Keith Vosseller (Department of Biochemistry & Molecular 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. Our lab has shown that 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. In addition, we are analyzing how O-GlcNAcylation regulates cancer metabolomics.
See all of Dr. Reginato's publications in PubMed.
"HER2/neu (erbB2) requires HIF-1 for mammary tumor growth and anoikis resistance"
Whelan KA, Schwab LP, Karakashev S, Franchetti L, Johannes GJ, Seagroves TN, and Reginato MJ
"ErbB2, FoxM1, and 14-3-3ζ prime breast cancer cells for invasion in response to ionizing radiation"
Kambach DM, Sodi VL, Lelkes PI, Azizkhan-Clifford J, and Reginato MJ
Oncogene (in press) (2012).
"Control of FLIPL expression and TRAIL resistance by the extracellular signal regulated kinase (ERK)1/2 pathway in breast epithelial cells"
Yerbes R, López-Rivas A, Reginato MJ, and Palacios C
Cell Death Differ. Dec; 19:1908-16 (2012).
"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
J. Biol. Chem. Mar 30; 287: 11070-81 (2012).
"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
Mol. Cancer Research, Feb; 10: 183-96. (2012).
"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)
Study links cancer growth to sugar-based modification found naturally in the body
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