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.