Abstract P5-15-05: The expression of genes involved in cholesterol biosynthesis is heterogeneous in breast cancer and may predict sensitivity to statin treatment and clinical outcome

Abstract

Abstract Background: Epidemiological evidence supports a protective role of cholesterol lowering drugs against breast cancer recurrence. Preclinical studies also support this role since statins can suppress breast cancer progression in various models. The response of breast cancer cells to statin treatment is however heterogeneous. We performed a comprehensive molecular characterisation of the anti-cancer mechanisms of statins in-vitro in view of identifying biomarkers of statin sensitivity in breast cancer. Methods: Breast cancer cell lines were treated with atorvastatin and the effects on cell proliferation were determined. A panel of cell lines displaying a diverse range of sensitivity to atorvastatin treatment were selected for gene expression microarray profiling following treatment. Differentially expressed genes were identified and subjected to gene ontology analysis and links to outcome following breast cancer diagnosis were explored. Results: Statin treatment elicited a more potent inhibition of proliferation in estrogen receptor (ER) negative cell lines. This was reflected on the whole genome transcriptional scale as the ER negative cells also displayed a more robust dysregulation of mRNA transcripts relative to the less-sensitive ER expressing cells. Down-regulation of DNA replication, regulation of cell cycle progression, and other proliferation-associated biological processes via mechanisms influencing the transcriptional activity of E2F was observed in the statin-sensitive cells. Importantly, cholesterol biosynthesis via the mevalonate pathway was upregulated in all cell lines following statin treatment. This effect was directly correlated with the pre-treatment expression levels of target genes involved in this biological process, suggesting a link with sensitivity to statin treatment. The expression of cholesterol biosynthesis genes was also found to be variable in primary breast tumors and a significant association was observed between decreased expression and an improved recurrence-free and overall survival, especially in ER positive tumors. Conclusions: These data suggest that the normal feedback regulation of the mevalonate pathway induced by statins may be compromised in a subset of breast cancer cells and may be exploited to predict breast cancer prognosis and sensitivity to statin treatment. Citation Format: Kimbung S, Feldt M, Bosch A, Borgquist S. The expression of genes involved in cholesterol biosynthesis is heterogeneous in breast cancer and may predict sensitivity to statin treatment and clinical outcome. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-15-05.