Abstract
BackgroundThe inhibitor of apoptosis (IAP) protein Survivin and its splice variants are differentially expressed in breast cancer tissues. Our previous work showed Survivin is released from tumor cells via small membrane-bound vesicles called exosomes. We, therefore, hypothesize that analysis of serum exosomal Survivin and its splice variants may provide a novel biomarker for early diagnosis of breast cancer.MethodsWe collected sera from forty breast cancer patients and ten control patients who were disease free for 5 years after treatment. In addition, twenty-three paired breast cancer tumor tissues from those same 40 patients were analyzed for splice variants. Serum levels of Survivin were analyzed using ELISA and exosomes were isolated from this serum using the commercially available ExoQuick kit, with subsequent Western blots and immunohistochemistry performed.ResultsSurvivin levels were significantly higher in all the breast cancer samples compared to controls (p < 0.05) with exosome amounts significantly higher in cancer patient sera compared to controls (p < 0.01). While Survivin and Survivin-∆Ex3 splice variant expression and localization was identical in serum exosomes, differential expression of Survivin-2B protein existed in the exosomes. Similarly, Survivin and Survivin-∆Ex3 proteins were the predominant forms detected in all of the breast cancer tissues evaluated in this study, whereas a more variable expression of Survivin-2B level was found at different cancer stages.ConclusionIn this study we show for the first time that like Survivin, the Survivin splice variants are also exosomally packaged in the breast cancer patients’ sera, mimicking the survivin splice variant pattern that we also report in breast cancer tissues. Differential expression of exosomal-Survivin, particularly Survivin-2B, may serve as a diagnostic and/or prognostic marker, a “liquid biopsy” if you will, in early breast cancer patients. Furthermore, a more thorough understanding of the role of this prominent antiapoptotic pathway could lead to the development of potential therapeutics for breast cancer patients.
Highlights
The inhibitor of apoptosis (IAP) protein Survivin and its splice variants are differentially expressed in breast cancer tissues
Moderate to high serum levels of Survivin were detected in 86% of triple negative (ER-Progesterone receptor (PR)-Her2-) breast cancer, and 83% of patients with Estrogen receptor (ER) and PR positive, Her2 negative (ER + PR + Her2-) receptor status (Table 2)
We found that Survivin-2B expression was inversely related to tumor grade in breast cancer patient tissues or exosomes compared to Survivin and Survivin-ΔEx3
Summary
The inhibitor of apoptosis (IAP) protein Survivin and its splice variants are differentially expressed in breast cancer tissues. Hypothesize that analysis of serum exosomal Survivin and its splice variants may provide a novel biomarker for early diagnosis of breast cancer. Survivin-2B is characterized by introducing a new exon of 69 bp with proapoptotic activity. Survivin-ΔEx3 has exon 3 excluded, and like the wild type, carries antiapoptotic activity. Survivin-3B has inclusion of a part of intron 3, preserving a complete BIR domain with antiapoptotic activity. Survivin and its splice variants are found to be associated with aggressive phenotypes of cancers [11] and may, if not prognostic, one day be considered like Her and hormone receptor to be predictive variables of breast cancer [3]
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