Aven blocks DNA damage-induced apoptosis by stabilising Bcl-xL

Induction of apoptosis by DNA-damaging agents involves the activation of mitochondrial apoptotic pathway. Aven has been identified as an antiapoptotic protein and has been shown to activate ATM in response to DNA damage. In this study, we demonstrated that enforced expression of Aven blocks UV-irradiation-, SN-38- or cisplatin-induced apoptosis upstream of mitochondria by stabilising Bcl-xL protein levels in breast cancer cells. Aven silencing by RNA interference markedly enhanced apoptotic response following treatment with DNA-damaging agents. Aven is complexed with Bcl-xL in untreated breast cancer cells and treatment with DNA-damaging agents led to decreased Aven/Bcl-xL interaction. Importantly, Bcl-xL was necessary for the prosurvival activity of Aven and depletion of Bcl-xL abrogated Aven-mediated protection against DNA damage-induced apoptosis. Analysis of breast cancer tissue microarrays revealed decreased Aven nuclear expression in breast cancer tissues compared with non-neoplastic breast tissues. In particular, we detected reduced nuclear expression of Aven in infiltrating ductal carcinoma and papillary carcinoma breast cancer subtypes compared with non-neoplastic breast tissues and infiltrating lobular breast cancer tissues. Our results suggest that Aven is an important mediator in DNA damage-induced apoptotic signalling in breast cancer cells and its nuclear expression is altered in breast cancer tissues, which may contribute to genomic instability in breast cancer tumours

Prognostic impact of tumor lymphocytic infiltrates in patients with breast cancer undergoing neoadjuvant chemotherapy

WOS: 000361421900007PubMed ID: 26416041Purpose: The presence of a pronounced tumor lymphocytic infiltrate (TLI) is deemed to reflect the presence of an immunoinflammatory response against the tumor and may thus have prognostic significance. We investigated the prognostic value of TLI detected in pathological specimens collected following neoadjuvant chemotherapy (NACT) in patients with breast cancer. Methods: 100 consecutive patients with breast cancer (mean age 47.8 +/- 11.4 years) who were scheduled to undergo anthracycline- and/or taxane-containing NACT were enrolled. Specimens collected after NACT were scored with the 4-point Klintrup scoring criteria for the presence of TLI. Results: 60 patients had low-grade TLI and 40 high-grade TLI. Comparison of the patient population according to low-grade vs high-grade TLI revealed statistically significant difference both in terms of disease-free survival (DFS) (log rank=4.28, p<0.05) and overall survival (OS) (log rank=3.96, p<0.05), with high-grade TLI patients showing a better prognosis. Multivariate Cox regression analysis identified postoperative tumor size and low-grade TLI as the two main independent adverse prognostic factors. Conclusion: High-grade TLI may interfer with tumor growth and can represent a favorable prognostic factor in women with breast cancer undergoing NACT

Long noncoding RNA MALAT1 may be a prognostic biomarker in IDH1/2 wild-type primary glioblastomas

Primary glioblastoma (GB) is the most aggressive type of brain tumors. While mutations in isocitrate dehydrogenase (IDH) genes are frequent in secondary GBs and correlate with a better prognosis, most primary GBs are IDH wild-type. Recent studies have shown that the long noncoding RNA metastasis associated lung adenocarcinoma transcript-1 (MALAT1) is associated with aggressive tumor phenotypes in different cancers. Our aim was to clarify the prognostic significance of MALAT1 in IDH1/2 wild-type primary GB tumors. We analyzed IDH1/2 mutation status in 75 patients with primary GB by DNA sequencing. The expression of MALAT1 was detected in the 75 primary GB tissues and 5 normal brain tissues using reverse transcription quantitative PCR (RT-qPCR). The associations between MALAT1 expression, IDH1/2 mutation status, and clinicopathological variables of patients were determined. IDH1 (R132H) mutation was observed in 5/75 primary GBs. IDH2 (R172H) mutation was not detected in any of our cases. MALAT1 expression was significantly upregulated in primary GB vs. normal brain tissues (p = 0.025). Increased MALAT1 expression in IDH1/2 wild-type primary GBs correlated with patient age and tumor localization (p = 0.032 and p = 0.025, respectively). A multivariate analysis showed that high MALAT1 expression was an unfavorable prognostic factor for overall survival (p = 0.034) in IDH1/2 wild-type primary GBs. High MALAT1 expression may have a prognostic role in primary GBs independent of IDH mutations