HER2 overcomes PTEN (loss)-induced senescence to cause aggressive prostate cancer

Abstract

Prostate cancer (CaP) is the most common cancer among adult men in the Western world. Better insight into its tumor-activating pathways may facilitate the development of targeted therapies. In this study, we show that patients who develop prostate tumors with low levels of PTEN and high levels of HER2/3 have a poor prognosis. This is functionally relevant, as targeting Her2 activation to the murine prostate cooperates with Pten loss and drives CaP progression. Mechanistically, this is associated with activation of the MAPK pathway and abrogation of the Pten loss-induced cellular senescence program. Importantly, inhibition of MEK function strongly suppressed proliferation within these tumors by restoring the Pten loss-induced cellular senescence program. Taken together, these data suggest that stratification of CaP patients for HER2/3 and PTEN status could identify patients with aggressive CaP who may respond favorably to MEK inhibition.

microRNA-143/145 loss induces Ras signaling to promote aggressive Pten-deficient basal-like breast cancer

“…Indeed, our group showed that combined deletion or mutation in p53 cooperates with pten deficiency to accelerate aggressive, transplantable TNBC-like tumors (13,62). As noted, prostatespecific inactivation of pten also induces benign tumors with increased p53-dependent senescence (11,12). Likewise, in models of biliary tract malignancies and von Hippel-Lindau (VHL) disease, murine pten inactivation either fails to induce tumors or elicits low-grade lesions (65,66).…”

“…In PTEN hamartoma tumor syndromes (PHTSs) like Cowden and Bannayan-RileyRuvalcaba, inherited autosomal mutations in PTEN lead to noncancerous tumor-like growths called hamartomas (10). In mouse models, prostate-specific inactivation of pten induces benign tumors with increased senescence, which is bypassed by concomitant inactivation of the tumor suppressor p53 (11,12). While pten deletion in mouse mammary epithelium leads to tumor formation (13), little is known about the tumorigenic potential of these lesions or of cooperating oncogenes/tumor suppressors that induce malignant…”

Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression

“…Failing to detect significant mutations or amplifications of RTKs, integrated genomic analyses have highlighted the involvement of PI3K/AKT and RAS/ERK pathways at a relatively high frequency (43%) in primary PC and almost universally in metastatic disease (2). Dual activation of PI3K and RAS pathways has been implicated in bypassing primary tumorsuppressive responses such as growth arrest and senescence (3,4). Interestingly, expression of phosphatase and tensin homolog (PTEN) and sprouty2 (SPRY2), key negative feedback regulators of the PI3K and RAS cascades, is decreased at higher frequencies than mutational activation of oncogenes such as PI3KCA, KRAS, and BRAF (2,5).…”

Sleeping Beautyscreen revealsPpargactivation in metastatic prostate cancer

“…Several genes cooperate with Pten loss to induce tumorigenesis in mice, including either loss of tumor suppressors such as Smad4 or Tp53 or activation of Erbb2 or Erg. However, none of these tumors fully reflect the continuum of human CaP (6)(7)(8)(9).…”