EHD2 is a Predictive Biomarker of Chemotherapy Efficacy in Triple Negative Breast Carcinoma

Abstract

EHD2 is a mechanotransducing ATPase localized in caveolae invaginations at the plasma membrane. EHD2 has recently been associated with several human cancers, however the significance of EHD2 transcript levels in cancer prognosis remains debated. Breast cancer is the most commonly occurring cancer in women and prognosis is variable depending on the subtypes. Triple negative breast cancer (TNBC) often has a poor therapeutic response. The aim of this study was to assess the prognostic significance of EHD2 transcripts and protein expression levels in breast carcinomas. We found that low EHD2 levels were associated with enhanced proliferation, migration and invasion of TNBC cells. EHD2 expression was significantly reduced in TNBC tissues and the loss of EHD2 led to higher expression of the pro-tumoral cytokine IL-8. In apparent contradiction with in vitro data, multivariate analysis of two independent cohorts of breast cancer patients revealed that low EHD2 was in fact associated with good prognosis in the highly proliferative TNBC subtype. Accordingly, TNBC low EHD2 expressers were found to benefit the most from chemotherapy when compared to all subtypes of breast cancers. Our study validates EHD2 expression level as an independent prognostic factor of metastasis-free survival and as a new predictive marker of chemotherapy efficacy in TNBC patients.

EHD2 overexpression promotes tumorigenesis and metastasis in triple-negative breast cancer by regulating store-operated calcium entry

“…1D ). Thus, our results indicate that high cytoplasmic EHD2 expression, a localization similar to that observed in normal mammary epithelium and BC cell lines, is a marker of more aggressive BC, contrary to published reports that did not assess the cytoplasmic/nuclear distribution of EHD2 and suggested its potential tumor suppressor role (11, 16, 22).…”

“…Our results differ from reports that reduction in EHD2 expression correlates with tumor progression in BC (11,22). Notably, a recent study, while it reported the depletion of EHD2 to an increase the oncogenic traits of BC cell lines in vitro, found low EHD2 expression in breast tumors to specify good prognosis and better chemotherapy response (16). Several factors could account for the discordance, including the lack of antibody validation of antibodies in prior studies, the high EHD2 expression in normal mammary adipocytes (Supplementary Fig.…”

“…Several factors could account for the discordance, including the lack of antibody validation of antibodies in prior studies, the high EHD2 expression in normal mammary adipocytes ( Supplementary Fig. S1A-B ), resulting in apparent reduction in EHD2 expression in tumor tissue using western blotting (11, 16, 22), and the possibility that EHD2 signals in prior studies represented nuclear EHD2, which we find is associated with positive prognostic factors ( Fig. 1B, Supplementary Table 1 ).…”

“…Studies of clear cell renal cell carcinoma also supported a positive role of EHD2 in tumorigenesis (15). A recent study provided a more mixed picture, with loss of EHD2 expression in TNBC cell lines enhancing their proliferation, migration, and invasion but low levels of EHD2 mRNA in TNBC patient tumors predicting better prognosis (16). Thus, a definitive role of EHD2 in oncogenesis and its mechanisms remain unclear.…”

EHD2 inhibits the invasive ability of lung adenocarcinoma and improves the prognosis of patients

“…Previous studies have shown that EHD2 may serve as a prognostic marker in breast cancer, papillary thyroid carcinoma, esophageal squamous cell carcinoma, and CRC ( 15 , 17 , 21 , 22 ). Furthermore, Shen et al reported that low EHD2 levels were associated with enhanced proliferation, migration, and invasion of triple negative breast cancer (TNBC) cells, and good prognosis in the highly proliferative TNBC subtype ( 23 ). In line with previous studies, we found that EHD2 was down regulated in LUAD tissues and correlated with poor prognosis through comprehensive bioinformatics analysis.…”