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Overexpression of synuclein-? predicts lack of benefit from radiotherapy for breast cancer patients.

ABSTRACT: Although radiotherapy following mastectomy was demonstrated to reduce the recurring risk and improve the prognosis of patients with breast cancer, it is also notorious for comprehensive side effects, hence only a selected group of patients can benefit. Therefore, the screening of molecular markers capable of predicting the efficacy of radiotherapy is essential.We have established a cohort of 454 breast cancer cases and selected 238 patients with indications for postoperative radiotherapy. Synuclein-? (SNCG) protein levels were assessed by immunohistochemistry, and SNCG status was retrospectively correlated with clinical features and survival in patients treated or not treated with radiotherapy. Gene Set Enrichment Analysis (GSEA) and survival analysis for online datasets were also performed for further validation.Among patients that received radiotherapy (82/238), those demonstrating positive SNCG expression had a 55.0 month shorter median overall survival (OS) in comparison to those demonstrating negative SNCG expression (78.4 vs. 133.4 months, log rank ? (2) ?=?16.13; p?

SUBMITTER: Min L

PROVIDER: S-EPMC5011985 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Overexpression of synuclein-γ predicts lack of benefit from radiotherapy for breast cancer patients.

Min Li L Zhang Cheng C Ma Ruolan R Li Xiaofan X Yuan Hua H Li Yihao Y Chen Ruxuan R Liu Caiyun C Guo Jianping J Qu Like L Shou Chengchao C

BMC cancer 20160905

<h4>Background</h4>Although radiotherapy following mastectomy was demonstrated to reduce the recurring risk and improve the prognosis of patients with breast cancer, it is also notorious for comprehensive side effects, hence only a selected group of patients can benefit. Therefore, the screening of molecular markers capable of predicting the efficacy of radiotherapy is essential.<h4>Methods</h4>We have established a cohort of 454 breast cancer cases and selected 238 patients with indications for ...[more]

PMID: 27595752

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Project description:BackgroundMore than 50% of cancer patients are recommended to receive radiotherapy. Recommendations are based mainly on clinical and pathological factors and not intrinsic tumour radio-sensitivity. Use of radiotherapy according to predictive markers would potentially reduce costly over-treatment, and improve the treatment risk-benefit ratio and cancer outcomes. Tumour expression of the 26S proteasome has been reported to predict radiotherapy response: low expression was associated with higher rates of local recurrence after radiotherapy, suggesting that low proteasome expression and activity was associated with radio-resistance. However, this conclusion is at odds with the emerging use of proteasome inhibitors as radio-sensitizers. Our aim was to further analyse the relevance of 26S proteasome expression, focussing specifically on the PSMD9 subunit, in the largest clinical cohort to date, and to investigate the functional role of PSMD9 in radio-sensitivity in breast cancer cell lines.MethodsWe examined expression of PSMD9 using immunohistochemistry in a cohort of 157 breast cancer patients, including 32 cases (20.4%) that subsequently developed local recurrences. The value of expression as a prognostic or radiotherapy predictive marker was tested using Kaplan-Meier and Cox regression analyses. PSMD9 function was examined in breast cancer cell lines MCF7 and MDA-MB-231 using siRNA knock-downs and colony forming assays after irradiation.ResultsLow tumour PSMD9 expression was significantly associated with a reduced incidence of local recurrence in patients receiving adjuvant radiotherapy (univariate log rank p?=?0.02; multivariate regression p?=?0.009), but not in those treated without radiotherapy, suggesting that low PSMD9 expression was associated with relative tumour radio-sensitivity. In support of this, reduction of PSMD9 expression using siRNA in breast cancer cell lines in vitro sensitized cells to radiotherapy.ConclusionsWe conclude that PSMD9 expression may predict radiotherapy benefit, with low expression indicative of relative radio-sensitivity, the opposite of previous reports relating to 26S proteasome expression. Our conclusion is compatible with use of proteasome inhibitors as radio-sensitizers, and highlights PSMD9 as a potential target for radio-sensitizing drugs.

Dataset Information

Overexpression of synuclein-? predicts lack of benefit from radiotherapy for breast cancer patients.

Publications

Overexpression of synuclein-γ predicts lack of benefit from radiotherapy for breast cancer patients.

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