Myc succeeds Akt activation and is required for growth of metastatic prostate cancer. Myc succeeds Akt activation and is required for growth of metastatic.

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Myc succeeds Akt activation and is required for growth of metastatic prostate cancer. Myc succeeds Akt activation and is required for growth of metastatic prostate cancer. A, IHC analysis of pAkt (Ser473) in metastatic lung nodules of LV-Cre/Luci–injected PtenloxP/loxP;Trp53loxP/loxP mice reveals absence of pAkt activation. In contrast, Myc levels are strongly increased, especially in the cytoplasm (compared with prostate; Supplementary Fig. S3F). Note the apparent further Myc increase in castration-resistant disease (Fig. 6C) compared with this mock-castrated metastasis. Scale bar, 50 μm. B, top, typical live imaging of RV-Myc-Luci–injected Ptenhy/+ mice shows lower abdominal signals and absence of distant metastasis (in contrast to LV-Cre/Luci–injected PtenloxP/loxP;Trp53loxP/loxP mice; Fig. 3A). Note that Ptenhy/+ mice express only 75% Pten throughout their body. Bottom, Kaplan–Meier analysis of disease spread in indicated RapidCaP models reveals that Myc expression can drive local dissemination of prostate cancer and cooperate with Pten suppression. Log-rank (Mantel–Cox) testing shows that wt, Ptenhy/+, as well as negative control study arms, are significantly different (P = 0.004). C, autopsy analysis of RV-Myc-Luci–injected mice reveals local, mostly lower abdominal disease dissemination from prostate (yellow arrows) to secondary sites (green arrows), including local lymph nodes. Also see Supplementary Fig. S7C. D, treatment of metastasis in LV-Cre/Luci–injected PtenloxP/loxP;Trp53loxP/loxP mice using the Myc-antagonizing Brd4 inhibitor JQ1 (at 50 mg/kg/d) reveals regression of metastatic disease compared with the disease progression in DMSO-treated mice. E, quantification of disease regression from D shows significant effect on metastasis (*, P = 0.026) but not primary disease. Error bars, SD; N.S., not significant; DMSO, dimethyl sulfoxide. Hyejin Cho et al. Cancer Discovery 2014;4:318-333 ©2014 by American Association for Cancer Research