Abstract 3631: Secretory phospholipase A2-IIa is a target gene of the HER/HER2-elicited pathway and a potential plasma biomarker for poor prognosis of prostate cancer

Prostate cancer is the second leading cause of cancer death among men in the US. Currently, there is no validated noninvasive biomarker with high specificity and sensitivity for prostate cancer diagnosis and prognosis. Only one out of five biopsies is diagnosed with cancer in PSA positive (>4 ng/ml) patients, while many aggressive cancers fail to be detected by PSA screening. Although the value of PSA test in the active surveillance remains to be validated, clinicians rely on it for cancer monitoring due to the lack of alternatives. These clinical obstacles underscore the urgent need for new biomarkers and therapeutic targets. Previous studies showed that prostate cancer tissues overexpress secretory phospholipase A2 group IIa (sPLA2-IIa) and sPLA2-IIa expression levels are increased with cancer progression. We are the first to demonstrate that prostate cancer cells secrete sPLA2-IIa and androgen-independent prostate cancer LNCaP-AI cells, relative to androgen-dependent parental LNCaP cells, express and secrete significant higher levels of sPLA2-IIa. We explored the underlying mechanism of sPLA2-IIa overexpression and found that EGF and Heregulin-α enhanced expression of the sPLA2-IIa gene, which was mediated by HER2 and HER3 activation. sPLA2-IIa is a NF-kB target gene. The EGFR/HER2 dual inhibitor Lapatinib and the NF-kB inhibitor Bortezomib inhibited sPLA2-IIa expression and secretion. EGF and Heregulin-α stimulated expression of the sPLA2-IIa gene at the transcriptional level via HER/HER2-PI3K-Akt-NF-kB signaling. We further confirmed that human sPLA2-IIa secreted by LNCaP xenograft in tumor bearing nude mice reached detectable plasma concentrations, while it was not detectable in the control mice. More importantly, plasma sPLA2-IIa was elevated in prostate cancer patients. A Receiver Operating Characteristic (ROC) analysis of 134 patient plasma specimens revealed that high levels of plasma sPLA2-IIa, with the optimum cutoff value of 2.0 ng/ml, were significantly associated with high Gleason score (8∼10) relative to intermediate Gleason score (6∼7) prostate cancers and advanced relative to indolent cancers. The area under the ROC curve (AUC) was 0.73 and 0.74, respectively. In summary, we found that elevated HER/HER2-elicited signaling contributes to sPLA2-IIa overexpression and secretion in prostate cancer cells. Our findings support the notion that high levels of plasma sPLA2-IIa may serve as a poor prognostic biomarker capable of distinguishing aggressive from indolent prostate cancers, which may improve decision-making and optimize patient management. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3631. doi:1538-7445.AM2012-3631