Cell-cell adhesion is a primary modulator of morphogenetic events during normal embryonic development. Metastatic dissemination of epithelial tumor cells is also strongly influenced by the activity of cell-cell adhesion molecules, in particular members of the cadherin family. My laboratory has shown that N-cadherin, a cadherin involved in dynamic processes such as cell migration and neurite outgrowth, is upregulated in invasive breast cancer cells and promotes metastasis of breast cancer cell lines. In contrast, E-cadherin, known to promote stable epithelial contacts, is lost during metastatic progression. Our data suggest that cadherin switching during tumor progression has a broader consequence than a simple change in cell-cell adhesion. The shift in cadherin expression also affects proteolytic activity of cells, their migration, invasiveness and metastasis. We and others have shown that even in the presence of E-cadherin, and strong cell-cell adhesiveness, N-cadherin can convert poorly invasive breast cancer cell lines into invasive and metastatic tumors, thus suggesting a dominant role for N-cadherin in this process. These effects of N-cadherin are mainly due to a functional cooperation with the FGF receptor resulting in epithelial to mesenchymal transition, cell signaling and morphological changes leading to metastasis. Thus our hypothesis is that N-cadherin upregulation in tumor cells is a key step in a series of interdependent molecular changes which lead to metastasis.
More recently, we discovered that Retinal cadherin (R-cadherin), a classic cadherin highly expressed in the brain and retina is also present in the mammary epithelium. We showed that similarly to E-cadherin, R-cadherin acts as an invasion suppressor gene which is downregulated in invasive duct carcinomas. Moreover, R-cadherin knockdown in mammary gland tissue leads to disruption of morphogenesis and gain of metastastic properties. Conversely, R-cadherin expression in aggressive tumor cells suppresses invasion and metastasis, and restores glandular morphogenesis.
My laboratory is currently investigating: 1) the molecular basis for cooperation between N-cadherin and the FGF receptor responsible for epithelial to mesenchymal transition (EMT) and metastasis with the goal of obtaining functional inhibitors of metastasis. 2) Regulation of EMT and metastasis by the MAPK and AKT signaling pathways 3) the relationship between cell cycle progression and tumor metastasis. 4) The mechanism of HER2 therapeutic resistance in breast cancer. 5) Cancer stem cells and their role in breast cancer metastasis.
Kimita Suyama, PhD
Jiahong Yao, MD
Yulong Zhou, PhD
Hazan, R.B., Phillips, G.R., Qiao, R.F., Norton, L. and Aaronson, S.A. (2000). Exogenous expression of Ncadherin in breast cancer cells induces cell migration, invasion and metastasis. J. Cell Biol.148: 779-789. PMID: 10684258
Suyama, k., Shapiro I., Guttman, M., and Hazan, R.B (2002) A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. Cancer Cell. 2: 301-314. PMID: 12398894
Nagi C, Guttman M, Jaffer S, Qiao R, Keren R, Triana A, Li M, Godbold J, Bleiweiss IJ, Hazan R (2005). Ncadherin expression in breast cancer: correlation with an aggressive histologic variant-invasive micropapillary carcinoma. Breast Cancer Res & Treat. 94:225-232. PMID: 16258702
Triana A, Sen C, Wolfe D, and Hazan R (2005). Cadherins and catenins in clival chordomas: correlation of expression with tumor aggressiveness. Am J Surg Pathol .29:1422-1434. PMID: 16224208
Cohen I, Pappo O, Elkin M, San T, Bar-Shavit R, Hazan R, Peretz T, Vlodavsky I, Abramobitz, R. (2006) Heparanase promotes growth, angiogenesis, and survival of primary breast tumors. Int J Cancer.18:1609-17. PMID: 16217746
Hulit J, Suyama k, Chung S, Keren R, Agiostratidou G, Shan W, Dong X, Williams TM, Lisanti MP, Knudsen K, Hazan RB (2007). N-cadherin signaling potentiates mammary tumor metastasis via enhanced ERK activation. Cancer Res. 67:3106-16. PMID: 17409417
Agiostratidou, G, Li, M, Suyama, K., Keren, R, Chung, S, Badano.I , Qian, K., Hulit, J., Boumediene,B., Loudig, O., Phillips, G, Locker, J and Hazan, RB (2009). Loss of R-cadherin facilitates breast tumor progression and metastasis. Cancer Res. 69:5030-38. PMID: 1949127
Chung, S., Yao, J., Suyama, K., Bajaj, S., Qian, X., Loudig, O., Eliseo, E., Phillips, G., Hazan. R.B. (2013). Ncadherin promotes breast cancer cell migration through Akt3 suppression. Oncogene. 32(4):422-30. PMID:22410780
Qian, X., Hulit, J., Suyama, K., Belbin, T., Smirnova, T., Segall, J., Phillips, G., Norton L., Hazan. R.B. (2013). p21 CIP mediates reciprocal switching between proliferation and invasion during metastasis. Oncogene. 2012 Jul 2. PMID: 22751124
Kotorashvili, A., Ramnauth A., Liu, C., Lin, J., Ye, K., Kim, RS., Hazan, R., Rohan, T., Fineberg, S., Loudig, O. (2012). Effective DNA/RNA co-extraction for analysis of microRNAs, mRNAs, and genomic DNA from formalinfixed paraffin-embedded specimens. PLoS One. 7(4). PMID: 22514653
Hou, J., Rodriguez-Gabin, G., Samaweera, L., Hazan, R., Goldberg, G., Horwitz, SB., McDaid, H. (2012). Exploiting MEK Inhibitor- Mediated Activation of ERα for Therapeutic Intervention in ER-Positive Ovarian Carcinoma. PLoS One. 8(2). PMID: 23390495
Qian X, Anzovino A, Hulit J, Kim S , Suyama K, Chandiramani N, McDaid HM, Nagi C, Phillips GR, Norton L,Hazan RB. (2013). N-cadherin/FGFR Signaling Promotes Epithelial to Mesenchymal Transition and Tumor Initiating Potential in ErbB2-driven Breast Cancer. Oncogene. PMID: 23975425
Kim S, Yao J, Suyama K, Qian X, Qian BZ, Bandyopadhyay S, Loudig OD, De Leon-Rodriguez C, Zhou ZN, Segall JE, Macian F, Norton L, Hazan RB. (2014). Slug Promotes Survival during Metastasis through Suppression of Puma-Mediated Apoptosis. Cancer Research. PMID: 2483072
Jiang H, English BP, Hazan RB, Wu P, Ovryn B. (2015). Tracking surface glycans on live cancer cells with single-molecule sensitivity. Angew Chem Int Ed Engl. 2015 PMID: 25515330
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