Abstract
Survivin is a key member of the inhibitor of apoptosis protein family, and is considered a promising therapeutic target due to its universal overexpression in cancers. Survivin is implicated in cellular radiation response through its role in apoptosis, cell division, and DNA damage response. In the present study, analysis of publically available data sets showed that survivin gene expression increased with breast cancer stage (p < 0.00001) and was significantly higher in estrogen receptor-negative cancers as compared to estrogen receptor-positive cancers (p = 9e-46). However, survivin was prognostic in estrogen receptor-positive tumors (p = 0.03) but not in estrogen receptor-negative tumors (p = 0.28). We assessed the effect of a survivin dominant-negative mutant on colony-formation (2D) and mammosphere-formation (3D) efficiency, and radiation response in the estrogen receptor-positive MCF7 and estrogen receptor-negative SUM149 breast cancer cell lines. The colony-formation efficiency was significantly lower in the dominant-negative survivin-transduced cells versus control MCF7 cells (0.42 vs. 0.58, p < 0.01), but it was significantly higher in dominant-negative population versus control-transduced SUM149 cells (0.29 vs. 0.20, p < 0.01). A similar, non-significant, trend in mammosphere-formation efficiency was observed. We compared the radiosensitivity of cells stably expressing dominant-negative survivin with their controls in both cell lines under 2D and 3D culture conditions following exposure to increasing doses of radiation. We found that the dominant-negative populations were radioprotective in MCF7 cells but radiosensitive in SUM149 cells compared to the control-transduced population; further, Taxol was synergistic with the survivin mutant in SUM149 but not MCF7. Our data suggests that survivin modulation influences radiation response differently in estrogen receptor-positive and estrogen receptor-negative breast cancer subtypes, warranting further investigation.
Highlights
Survivin is the smallest member of the inhibitor of apoptosis protein (IAP) family at 16.5 kDa and is encoded by BIRC5 [1]
We investigated the relevance of survivin to breast cancer by extracting BIRC5 expression information from three public databases: Oncomine [22], Gene Expression-Based Outcome for Breast Cancer Online (GOBO) [23], and Kaplan-Meier Plotter (K-M Plot) [25]
We found that BIRC5 was expressed significantly higher in invasive breast carcinoma compared to normal breast doi:10.1371/journal.pone.0120719.g001
Summary
Survivin is the smallest member of the inhibitor of apoptosis protein (IAP) family at 16.5 kDa and is encoded by BIRC5 (baculoviral inhibitor of apoptosis repeat-containing protein-5) [1]. It is implicated in the regulation of several cellular networks, and is prominent for its universal overexpression in human cancers. A more recent study reported that survivin expression could function as a predictive biomarker of complete pathologic response to neoadjuvant chemotherapy in patients with stage II or stage III breast cancer [5]. Retrospective analysis of clinical trials from which these studies were validated revealed the recurrence score predicts for risk of local recurrence among patients treated with lumpectomy and radiation [7]
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