SIRT5 as a biomarker for response to anthracycline-taxane-based neoadjuvant chemotherapy in triple-negative breast cancer

Abstract

Neoadjuvant chemotherapy (NAC) is of great importance for patients with triple-negative breast cancer (TNBC) and the achievement of pathological complete response (pCR) to NAC in TNBC patients indicates survival benefits. However, the identification of reliable predictive biomarkers of pCR to NAC in TNBC patients remains an urgent and largely unattended medical issue. In the present study, we evaluated the differentially expressed genes (DEGs) between pCR and non-pCR patients after doxorubicin/cyclophosphamide therapy, followed by paclitaxel pre-operative treatment in 64 TNBC patients recorded in the GSE41998 dataset of Gene Expression Omnibus and identified 118 DEGs. Subsequently, we selected five core genes that were closely associated with the pCR of TNBC patients by using a genetic algorithm‑support vector machine-based method. Sirtuin 5 (SIRT5) was one of the five core genes and patients who achieved pCR expressed higher levels of SIRT5. Thus, we speculated that SIRT5 may be a potential predictive marker of the response to anthracycline-taxane-based chemotherapy. Oncomine analysis revealed that the expression levels of SIRT5 were higher in epirubicin/cyclophosphamide-docetaxel responders compared with non-responders. Furthermore, Gene Ontology analysis indicated that SIRT5 may affect the response to anthracycline-taxane-based chemotherapy by regulating the Rho pathway. It was also observed that SIRT5 was upregulated in TNBC and breast cancer with BRCA1 mutation subtypes. High SIRT5 expression was also associated with poor clinical outcomes of breast cancer patients. In conclusion, the present study revealed SIRT5 as a biomarker for response to anthracycline-taxane-based NAC in patients with TNBC and identified a series of novel biological functions of SIRT5 in breast cancer.

The Roles of Sirtuin Family Proteins in Cancer Progression

“…Only a limited amount of research has been conducted on SIRT5 in tumorigenesis. Several recent studies have shown that SIRT5 may play a tumor-promoting role in multiple types of cancer, such as HCC [65], colon cancer [63], human osteosarcoma [63] and breast cancer [149]. Moreover, the SIRT5 gene frequently shows an increase in duplication in specific cancer types, including uterine cancer, breast cancer, cutaneous and uveal melanomas, lung cancer, and lymphoma [150].…”

The sirtuin family in cancer

“…In breast cancer, higher SIRT5 expression was associated with increased metastasis risk and lower 1-year survival. In turn, the same report showed that breast cancer patients expressing higher levels of SIRT5 responded better to the standard chemotherapy epirubicin/cyclophosphamidedocetaxel [186].…”

“…These posttranslational modifications have been shown to exert pro-or anti-tumoral effects, depending on the context. SIRT5 mRNA or protein have been found upregulated in non-small cell lung cancers (NSCLC) [182], Waldenström macroglobulinemia [183], hepatocellular carcinoma (HCC) [184], colorectal carcinoma 185, and breast cancer [186,187]. In turn, SIRT5 mRNA or protein levels were shown to be downregulated in HCC [188], endometrium [189] or head and neck squamous carcinomas [190].…”

<p>Predictors of Neoadjuvant Chemotherapy Response in Breast Cancer: A Review</p>

“…SIRT5 upregulation in various degrees may be specific to certain histological subtypes, and SIRT5 mRNA in high level may imply the good prognosis. 72 The findings by Abdel and al., showed that gene copy number aberration, transcript and protein on sperm-associated antigen 5 (SPAG5) were connected with poor prognosis, such as TP53 mutation, PAM50-LumB phenotype, and PAM50-HER2 phenotype. As predictive markers in breast cancer, both SPAG5 transcript and protein may be the key point for chemo-response.…”