Identifying molecular features that distinguish fluvastatin-sensitive breast tumor cells

Abstract

Statins, routinely used to treat hypercholesterolemia, selectively induce apoptosis in some tumor cells by inhibiting the mevalonate pathway. Recent clinical studies suggest that a subset of breast tumors is particularly susceptible to lipophilic statins, such as fluvastatin. To quickly advance statins as effective anticancer agents for breast cancer treatment, it is critical to identify the molecular features defining this sensitive subset. We have therefore characterized fluvastatin sensitivity by MTT assay in a panel of 19 breast cell lines that reflect the molecular diversity of breast cancer, and have evaluated the association of sensitivity with several clinicopathological and molecular features. A wide range of fluvastatin sensitivity was observed across breast tumor cell lines, with fluvastatin triggering cell death in a subset of sensitive cell lines. Fluvastatin sensitivity was associated with an estrogen receptor alpha (ERα)-negative, basal-like tumor subtype, features that can be scored with routine and/or strong preclinical diagnostics. To ascertain additional candidate sensitivity-associated molecular features, we mined publicly available gene expression datasets, identifying genes encoding regulators of mevalonate production, non-sterol lipid homeostasis, and global cellular metabolism, including the oncogene MYC. Further exploration of this data allowed us to generate a 10-gene mRNA abundance signature predictive of fluvastatin sensitivity, which showed preliminary validation in an independent set of breast tumor cell lines. Here, we have therefore identified several candidate predictors of sensitivity to fluvastatin treatment in breast cancer, which warrant further preclinical and clinical evaluation.

Global Transcriptional Changes Following Statin Treatment in Breast Cancer

“…Gene ontology and pathway analyses identified deregulated biologic processes using significantly differentially expressed genes following statin treatment as input currently being tested in more than 50 clinical trials, both in the preventive and adjuvant treatment settings (http://www.clinicaltrials.gov). The identification of predictive biomarkers for statin efficacy is essential, considering the heterogeneous nature of breast cancer, as demonstrated in vitro in cell lines displaying substantial differences in statin susceptibility (1,23). Furthermore, the mechanisms behind the anticancer effects induced by statins are not fully understood, and translational studies within clinical trials addressing the biologic effects of statins are needed (24).…”

Establishment and characterization of a bladder cancer cell line with enhanced doxorubicin resistance by mevalonate pathway activation

“…Another complication is a substantial interindividual heterogeneity in therapeutic response to statins [20]. Cell line collections have been used to define the biological basis of statin sensitivity in multiple myeloma [40] and breast carcinoma [41], and we believe that our pair of cell lines could be similarly helpful within the context of urothelial carcinoma. Statin use for cancer treatment thus follows the personalized treatment paradigm.…”

Triple-negative breast cancer: is there a treatment on the horizon?

“…Goard et al . characterized fluvastatin sensitivity in 19 breast cancer cell lines and found that fluvastatin sensitivity was strongly associated with an ERα-negative status and the basal-like phenotype [83]. Xenografts of ERα-negative tumor cells have also been shown to respond to treatment with lipophilic statins, including simvastatin and fluvastatin [79, 81].…”