Abstract P6-07-18: Identification of Sperm Associated Antigen 5 (SPAG5) as a novel biological and predictive biomarker in Breast cancer
Authors: TMA Abdel-Fatah, G Ball, AK Miles, P Moseley, A Green, B Rees, IO Ellis, SYT Chan
Journal: Cancer Research (2012)

Abstract Introduction: SPAG5 has been found to be involved in the functional and dynamic regulation of mitotic spindles, and to be essential for chromosome segregation fidelity. Recently we found by using neural network and pathways analysis of a gene expression array data that SPAG5 was among top 10 ranked genes out of 48,000 of transcripts, that accurately predicted worse clinical outcome based on a 10-fold external cross-validation analysis with an average classification accuracy of &amp;gt;99.999%. Moreover we found that 5% of BC showed amplification of SPAG5 locus at chromosome 17q11.2 and SPAG5 mRNA expression levels displayed a statistically significant correlation with its copy number. Methods: In the current study the molecular and clinicopathological features of SPAG5 expression and its effect on management of BC have been investigated in 2800 BC patients with primary operable invasive BCs constituted four cohorts: 1) A series of 1650 BC patients received adjuvant endocrine and/or CMF chemotherapy according to NPI.2) A series of 256 BC received adjuvant anthracycline-based chemotherapy (ATC-CT)3) A series of 140 primary BC HER2+ patients treated with ATC-CT+ Herceptin 4) To validate SPAG5 as a predictor factor for ATC-CT, 260 patients with locally advanced primary breast cancer treated with neoadjuvant ATC-CT were included and the pathological complete response (pCR) was used to evaluate the response to chemotherapy. Immunohistochemical staining was performed using Anti–SPAG5 rabbit polyclonal (HPA022479; Sigma). Results: i) By using dual immunoflurescent in BC cell lines, co-expression of SPAG5 and proliferating cell nuclear antigen (PCNA) was detected in 4 out of 5 of the breast cancer cell lines screened (MCF7, T47D, MDA468 and MDA231) providing evidence for the importance of SPAG5 in cell proliferation. ii) 20% of breast cancer showed SPAG5 protein overexpression. SPAG5 overexpression showed a statistically significant association with ER−, PR−, triple negative phenotype, high grade tumour, high ki67, basal like phenotype and epithelial mesenchymal transition phenotype, p53 mutation and absence of DNA repair genes (BRCA1, ATM and XRCC1); p values &amp;lt;0.0001. iii) In high risk ER− BC patients who did not received any adjuvant therapy or received ineffective CMF chemotherapy, SPAG5+ protein expression had a similar risk of death and recurrence. Receiving ATC-CT had a positive impact on high risk ER− BC patients with SPAG5 protein + expression as SPAG5+ protein expression showed 72–65% less of death, recurrence and metastases compared to SPAG5−; p &amp;lt; 0.0001. The positive impact of ATC-CT on SPAG5+BC has also been confirmed in HER2+ who either received ATC-CT only or ACT-CT plus Herceptin. iv) Moreover, BC received neoadjuvantATC-CT, SPAG5+ BC achieved 39% pCR vs., 6% of SPAG5-negative BC (p &amp;lt; 0.00001). After controlling to other validated predictors for pCR, SPAG5 remained as a powerful independent predictor (HR; 2.4, CI 95%; 1.5–3.9; p = 0.00001). Conclusion: SPAG5 is an important novel gene implicated in the survival of BC cells and its protein expression is an independent predictor for ATC- CT. SPAG5 may provide new avenues for the discovery of new predictive marker to guide therapeutic intervention. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-18.