Cancer researchers are facing a deluge of genome data. Turning this powerful information into our advantage ultimately depends on highly reliable systems for experimental validation. Our study shows how data from large scale genomics can be put into a meaningful biological context and transformed into actionable information by comparison with results from hypothesis driven research in genetically engineered mice.
First, we have identified in PHLPP1
, a ‘druggable’ suppressor of prostate cancer progression since its antagonist, mTORC2 can be pharmacologically inhibited. Most importantly, genetic mTORC2-inactivation has no adverse effects on adult prostate tissue (Guertin and Sabatini, 2009
). The deletion involving PHLPP1
(18q21) contains still other suspected and confirmed tumor suppressors. The TGF-beta effectors SMAD2, SMAD4, SMAD7, as well as the DCC
gene, are co-deleted in the majority of cases. The cooperation of Smad4
with complete Pten
-loss in prostate cancer has recently been shown in knockout mice (Ding et al., 2011
) and similarly, we find Smad-activation in response to Phlpp1
-loss in prostate. The co-deletion of SMAD4
could thus conceivably exacerbate the consequences of PTEN
-loss in human prostate.
Second, our study reveals a progression principle of PTEN-pathway driven aggressive prostate cancer. After its initial discovery (Chen et al., 2005
), the senescence response in prostate was primarily thought to protect early hyperplastic precursor lesions from becoming clinically relevant cancer (reviewed in (Narita and Lowe, 2005
)). In contrast, our genomic analysis reveals that strong activation of the pathway coincides with p53-deletion in metastasis, not cancer. Therefore we propose that primary prostate lesions must and do
develop in PTEN
haploinsufficiency (75% show reduction in protein) in order to fly below the radar of the p53 activation system unless a p53 alteration has already occurred.
Third, we find that low PTEN/PHLPP1
transcription correlates with biochemical relapse in patients after prostate surgery. If confirmed in expanded studies, this finding could yield important molecular information that might be used to stratify patients for PI 3-Kinase inhibitor trials. Importantly, recent results (Carver et al., 2011
; Mulholland et al., 2011
) have revealed that blockade of AR- or PI 3-Kinase signaling is mutually reinforcing, demonstrating the need for combined therapeutic pathway inactivation. Intriguingly, this research has shown that AR-mediated AKT-inhibition is carried out by PHLPP1 activation since PHLPP1 is degraded by AR blockade, a mainstay of advanced prostate cancer therapy. These results reinforce the crucial role of PHLPP1 status in prostate cancer progression.
Finally, we identify the PHLPP2 protein as part of a cell autonomous fail-safe mechanism, which in concert with p53 responds to excessive pathway signaling in prostate. The activation of these responses cannot prevent tumorigenesis in our animal system, yet they critically shape the disease time course in a model where, unlike in human, every prostate cell is engineered to suffer Pten/Phlpp1-loss. The PHLPP2-mediated negative pathway feedback represents another potential mechanism by which mTORC1 activation inhibits AKT activity. Since the pharmacological inhibition of mTorc1 is able to derail this response, our data argue for checking thisPHLPP2 activation in patients before they receive mTORC1-targeting pathway therapy.
Taken together, our results identify the critical role of the PHLPP proteins in prostate cancer and suggest that defining their status in relation to PTEN and p53 is important for understanding and combatting the disease.