Our laboratory studies the the EGF-CFC family and their role in the development of the mouse mammary gland and in the initiation and progression of mouse and human breast cancer. The EGF-CFC family has been identified in all chordate species and consists of Cripto-1 (CR-1) and Cryptic that perform an obligatory role as co-receptors for the TGF beta subfamily of proteins, Nodal/GDF1/GDF3 and that regulate gastrulation, germ layer formation and left-right axis determination. In addition, Nodal and Cripto-1 are essential in the maintenance of embryonic stem cell (ES) self renewal and pluripotency. Nodal binding to cripto-1 functions through the ALK4 and Act-R-IIB Activin/TGF beta class of serine-threonine kinase receptors to activate a canonical Smad2 and Smad3 intracellular signaling pathway through dimerization with Smad4. We have shown that human CR-1 is overexpressed in approximately 40-90% of a variety of human carcinomas including breast tumors. We have also found that overexpression of either Cr-1 or CR-1 in mouse mammary epithelial cells in vitro and in vivo as a transgene results in their transformation and in their enhanced ability to migrate and invade as a result of epithelial-mesenchymal transition (EMT). We were able to demonstrate that CR-1 can also activate Nodal and ALK4-independent signaling pathways by binding to glypican-1 and by subsequently activating c-src, MAPK, PI-3 kinase and Akt which are critical for CR-1 in stimulating EMT. We have also recently found that Cripto-1 can enhance canonical Wnt/beta-catenin signaling at limiting concentrations of Wnt by facilitating the binding of Wnt to the Lrp5 or Lrp6 co-receptors on the cell surface. Finally, we have found that two transcription factors, LRH-1 and GCNF, can positively and negatively regulate CR-1 expression, respectively, in human breast cancer cell lines. Expression of CR-1 was found to correlate with LRH-1 expression in a tissue microarray of human breast tumors and this correlation in LRH-1 and CR-1 expression occurs more frequently in HER+ and in triple negative breast tumors ( HER-, ER- and PR-) as compared to more differentiated Luminal A and Luminal B breast tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC009003-31
Application #
8763024
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
31
Fiscal Year
2013
Total Cost
$1,002,427
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Klauzinska, Malgorzata; Castro, Nadia P; Rangel, Maria Cristina et al. (2014) The multifaceted role of the embryonic gene Cripto-1 in cancer, stem cells and epithelial-mesenchymal transition. Semin Cancer Biol 29:51-8
di Bari, M G; Ginsburg, E; Plant, J et al. (2009) Msx2 induces epithelial-mesenchymal transition in mouse mammary epithelial cells through upregulation of Cripto-1. J Cell Physiol 219:659-66
Mancino, Mario; Esposito, Claudia; Watanabe, Kazuhide et al. (2009) Neuronal guidance protein Netrin-1 induces differentiation in human embryonal carcinoma cells. Cancer Res 69:1717-21
Bianco, Caterina; Strizzi, Luigi; Mancino, Mario et al. (2008) Regulation of Cripto-1 signaling and biological activity by caveolin-1 in mammary epithelial cells. Am J Pathol 172:345-57
Watanabe, Kazuhide; Nagaoka, Tadahiro; Strizzi, Luigi et al. (2008) Characterization of the glycosylphosphatidylinositol-anchor signal sequence of human Cryptic with a hydrophilic extension. Biochim Biophys Acta 1778:2671-81
Strizzi, Luigi; Abbott, Daniel E; Salomon, David S et al. (2008) Potential for cripto-1 in defining stem cell-like characteristics in human malignant melanoma. Cell Cycle 7:1931-5
Hirota, Morihisa; Watanabe, Kazuhide; Hamada, Shin et al. (2008) Smad2 functions as a co-activator of canonical Wnt/beta-catenin signaling pathway independent of Smad4 through histone acetyltransferase activity of p300. Cell Signal 20:1632-41
Strizzi, Luigi; Postovit, Lynne-Marie; Margaryan, Naira V et al. (2008) Emerging roles of nodal and Cripto-1: from embryogenesis to breast cancer progression. Breast Dis 29:91-103
Strizzi, Luigi; Mancino, Mario; Bianco, Caterina et al. (2008) Netrin-1 can affect morphogenesis and differentiation of the mouse mammary gland. J Cell Physiol 216:824-34
Bianco, Caterina; Mysliwiec, Margaret; Watanabe, Kazuhide et al. (2008) Activation of a Nodal-independent signaling pathway by Cripto-1 mutants with impaired activation of a Nodal-dependent signaling pathway. FEBS Lett 582:3997-4002

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