Supplementary Figure S5. IHC analysis of wild type lung and primary and metastatic tumors. (A) Wild type lung do not show increased Myc, pAktS473 or Phlpp2 staining comparing to metastatic lungs. Scale Bar, 100 Î¼m. (B) Il6 analysis of PC metastasis to lung revealed that metastatic nodules expressed Il6. Staining levels varied between 22.5% and 72.8% positive cells per nodule. (C) No Il6 activation is found in the p53-null setting and the Pten-null glands that were free of hyperplasia/ neoplasia, while the glands with proliferating cells showed Il6, consistent with their breaking of the p53 response in parts of the tissue (see the positive gland in the right bottom corner of Ptenpc-/-).
ARTICLE ABSTRACTWe have recently recapitulated metastasis of human PTEN/TP53–mutant prostate cancer in the mouse using the RapidCaP system. Surprisingly, we found that this metastasis is driven by MYC, and not AKT, activation. Here, we show that cell–cell communication by IL6 drives the AKT–MYC switch through activation of the AKT-suppressing phosphatase PHLPP2, when PTEN and p53 are lost together, but not separately. IL6 then communicates a downstream program of STAT3-mediated MYC activation, which drives cell proliferation. Similarly, in tissues, peak proliferation in Pten/Trp53–mutant primary and metastatic prostate cancer does not correlate with activated AKT, but with STAT3/MYC activation instead. Mechanistically, MYC strongly activates the AKT phosphatase PHLPP2 in primary cells and prostate cancer metastasis. We show genetically that Phlpp2 is essential for dictating the proliferation of MYC-mediated AKT suppression. Collectively, our data reveal competition between two proto-oncogenes, MYC and AKT, which ensnarls the Phlpp2 gene to facilitate MYC-driven prostate cancer metastasis after loss of Pten and Trp53.Significance: Our data identify IL6 detection as a potential causal biomarker for MYC-driven metastasis after loss of PTEN and p53. Second, our finding that MYC then must supersede AKT to drive cell proliferation points to MYC inhibition as a critical part of PI3K pathway therapy in lethal prostate cancer. Cancer Discov; 5(6); 636–51. ©2015 AACR.This article is highlighted in the In This Issue feature, p. 565