Elafin drives poor outcome in high-grade serous ovarian cancers and basal-like breast tumors

Abstract

High grade serous ovarian carcinoma (HGSOC) and basal-like breast cancer (BLBC) share many features including TP53 mutations, genomic instability and poor prognosis. We recently reported that Elafin is overexpressed by HGSOC and is associated with poor overall survival. Here, we confirmed that Elafin overexpression is associated with shorter survival in 1000 HGSOC patients. Elafin confers a proliferative advantage to tumor cells through activation of the MAP kinase pathway. This mitogenic effect can be neutralized by RNA interference, specific antibodies, and a MEK inhibitor. Elafin expression in patient-derived samples was also associated with chemoresistance and strongly correlates with bcl-xL expression. We extended these findings into examination of 1100 primary breast tumors and six breast cancer cell lines. We observed that Elafin is overexpressed and secreted specifically by BLBC tumors and cell lines, leading to a similar mitogenic effect through activation of the MAP kinase pathway. Here too, Elafin overexpression is associated with poor overall survival, suggesting that it may serve as a biomarker and therapeutic target in this setting.

Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection

“…5) Lastly, elafin may directly act on endothelial cells as a mitogenic molecule and promote angiogenesis. Informed by a recent publication, in which elafin was demonstrated to promote cancer cell proliferation in an ERK activation-dependent manner (35), we also found that elafin is capable of activating ERK in endothelial cells and promoting endothelial cell proliferation, migration and tube formation in a dose-dependent manner (Fig. 6).…”

“…Although elafin is better known as an inhibitor of neutrophil elastase, a very recent study revealed that this endogenous inhibitor can also directly promote tumor cell proliferation by activating the ERK mitogenic signaling pathway (35). We performed Western blot analysis of HUVECs and showed that elafin dose-dependently enhanced ERK1/2 activation (Fig.…”

RNA sequencing reveals differentially expressed genes as potential diagnostic and prognostic indicators of gallbladder carcinoma

“…As for its biological function in tumorigenesis, transcripts of PI3 are extremely abundant in glioblastoma patient samples and significantly correlated with dismal survival [ 29 ]. In ovarian and breast carcinoma, PI3 expression was also found to be transcriptionally up-regulated through activation of the NFκB and MEK/ERK signaling pathway, and correlate with unfavourable overall survival [ 30 ]. However, controversial report has already emerged that PI3 could suppress tumorigenesis through inhibition of elastase and thus could serve as a prognostic indicator in breast cancer [ 31 ].…”

Personalized medicine in hematology — A landmark from bench to bed

“…Also, most of the information provided by whole genome sequencing (WGS) cannot be fully interpreted [55,56] . Despite the fact that there are over 800 new small molecules on developmental pipeline [57–59] , the number of drugable targets currently available in clinics is less than 30 [59,60] . The economic impact of a large scale application of WGS along with limited clinical applicability of information obtained from whole genome is suggestive for the utilization of alternative tools for diagnostic purposes.…”