PAR Polarity Complex

We demonstrated that the human epidermal growth family receptor 2 (HER2/ErbB2) oncogene interacts with and disrupts the PARD3-PARD6-aPKC cell polarity complex (Nat Cell Biol, 2006, 8: 1235-45). An intact PARD6-aPKC complex was required for the ability of ErbB2 to transform 3D acini, whereas, it was not required for inducing aberrant proliferation. Thus cell polarity and cell proliferation pathways can be uncoupled from each other during initiation of transformation of mammary epithelial cells. More recently, we demonstrated that the cell polarity proteins function as metastasis suppressors (Nat Cell Biol. 2013, 15:189-200). We showed that loss of Pard3 cell polarity protein induced invasion and metastasis in vivo, by affecting cortical actin dynamics, decreasing E-cadherin junction maturation and cell-cell cohesion without inducing any detectable epithelial to mesenchymal transition. These studies are beginning to define a framework for how polarity proteins/pathways regulate oncogene-induced transformation of polarized breast epithelial cells.

MCF-10A acini: No HER2 activation

MCF-10A acini: plus HER2 activation

Relevant publications from our group:

Aranda, V., Haire, T., Nolan, M.E., Calarco, J.P., Rosenberg, A.Z., Fawcett, J.P., Pawson, T., and Muthuswamy, S.K., Par6-aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control. Nat Cell Biol, 8(11): p. 1235-45, 2006.

Nolan ME, Aranda V, Lee S, Lakshmi B, Basu S, Allred DC, Muthuswamy SK. The polarity protein Par6 induces cell proliferation and is overexpressed in breast cancer. Cancer Res. 2008 Oct 15;68(20):8201-9.

Lucs AV, Muller WJ, Muthuswamy SK. Shc is required for ErbB2-induced inhibition of apoptosis but is dispensable for cell proliferation and distruption of cell polarity. Oncogene. 2010 Jan 14;29(2):174-87. Epub 2009 Oct 12.

Chatterjee S, Seifried L, Feigin ME, Gibbons DL, Scuoppo C, Lin W, Rizvi ZH, Lind E, Dissanayake D, Kurie J, Ohashi P, Muthuswamy SK. Dysregulation of cell polarity proteins synergize with oncogenes or the microenvironment to induce invasive behavior in epithelial cells. PL0S One. 2012;7(4):e34343. Epub 2012 Apr 18.

Xue, B, Krishnamurthy, K, Allred, CA, Muthuswamy, SK. Loss of Par3 promotes breast cancer metastasis by compromising cell-cell cohesion. Nat Cell Biol. 2013 Feb;15(2):189-200.

Reviews:

Aranda V, Nolan ME, Muthuswamy SK. Par complex in cancer: a regulator of normal cell polarity joins the dark side. Oncogene, 2008 Nov 24;27(55):6878-87.

Feigin ME, Muthuswamy SK. Polarity proteins regulate mammalian cell-cell junctions and cancer pathogenesis. Curr Opin Cell Biol, 2009 Oct;21(5):694-700. Epub 2009 Sep 2.

Huang L, Muthuswamy S.K. Polarity protein alterations in carcinoma: a focus on emerging roles for polarity regulators. Curr Opin Genet Dev. 2010 Feb;20(1):41-50. Epub 2010 Jan 21.

Muthuswamy SK, Xue B. Cell polarity as a regulator of cancer cell behavior plasticity. Annu Rev Cell Dev Biol. 2012;28:599-625. doi: 10.1146/annurev-cellbio-092910-154244. Epub 2012 Aug 6.