In addition to cooperating with oncogenes, cell polarity proteins by themselves functions as modulators of cancer biology. We published the first report (Cell 2008, 135:865-78) that the cell polarity protein SCRIB functions as a tumor suppressor in mammary epithelia by inhibiting cell polarity, blocking three-dimensional morphogenesis, inhibiting apoptosis and inducing dysplasia in vivo. Subsequent studies by others have expanded on this observation and demonstrate that inactivation of SCRIB functions as a tumor suppressor in prostate and lung, implicating SCRIB as regulator of biology of multiple cancers.
However, we realized a paradox, SCRIB is frequently amplified (up to 30%) and mislocalized, (not lost/downregulated), in multiple carcinoma including breast, ovary, prostate, lung and head and neck. We recently reported (Cancer Res. 2014, 74:3180-94) that SCRIB interacts with PTEN and that expression of a mislocalized form SCRIB, but not the wild type protein, decreases membrane localization of PTEN and results in activation of PI3K signaling. Transgenic mice overexpressing a mislocalized form of SCRIB develop tumors with basal characteristics, demonstrating that mislocalized SCRIB can have a positive role during tumorigenesis. These studies provide a new perspective on the role on cell polarity proteins in cancer that they may not only function tumor suppressor due to loss-of-function, but can also have a gain-of-function by acting as a neomorph.
Relevant publications from our group:
Zhan L, Rosenberg A, Bergami KC, Yu M, Zuan Z, Jaffe AB, Allred C, Muthuswamy S.K. Deregulation of Scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma. Cell 2008 Nov 28; 135(5):865-78.
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.
Feigin, ME, Akshinthala, D, Araki, K, Rosenberg, AZ, Muthuswamy, LB, Martin, B, Lehmann, BD, Berman, HK, Pietenpol, JA, Cardiff, RD and Muthuswamy, SK. Mislocalization of the cell polarity protein Scribble promotes mammary tumorigenesis and is associated with basal breast cancer. Cancer Res. 2014 Jun 1;74(11):3180-94.
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.