Abstract PD03-07: Statin-induced decrease in proliferation depends on HMG-CoA reductase expression in breast cancer
Authors: Bjarnadottir O , Romero Q , Bendahl P-O , Rydén L , Rose C , Loman N , Uhlén M , Jirström K , Grabau D , Borgquist S 
Published: August 2014

Background: Lipophilic statins proposedly harbour anti-tumoral effects in breast cancer by decreasing proliferation and increasing apoptosis. Although the biological mechanisms are not fully elucidated, HMG-CoA reductase (HMGCR) is the well-recognized target of statins. HMGCR is the rate-limiting enzyme of the mevalonate pathway, which produces cholesterol, steroid-based hormones and non-sterol isoprenoids. Previous studies demonstrated an inter-tumoral variation of HMGCR expression, suggesting HMGCR as a prognostic marker. HMGCR activity, in response to statin treatment as evaluated in MCF7 breast cancer cells, showed an adaptive induction of HMGCR activity. To our knowledge, no in vivo statin-induced effects on HMGCR activity have been reported. Furthermore, the potential of HMGCR as a predictive marker for statin treatment needs to be addressed.

Aim: To validate the statin-induced anti-proliferative effects while investigating the HMGCR response and the impact of HMGCR as a statin-predictive marker in invasive breast cancer.

Design and Methods: The study was designed as a single-center window-of-opportunity trial including patients with primary invasive breast cancer and a minimum tumor size of 15 mm. The trial was powered to include 50 patients. Following core needle biopsies, patients were prescribed high-dose atorvastatin (80 mg/day) during two weeks prior to surgery. Pre- and post treatment tumor samples were stored as paraffin imbedded tissue blocks. Proliferation was investigated by Ki67 expression using the MIB-1 antibody, counting 400 tumor cells per sample. The cytoplasmic intensity of HMGCR expression (negative, weak, moderate, strong) was determined using the monoclonal antibody HPA-8338. Change in Ki67 expression following statin treatment was the primary end-point and HMGCR activity alterations a secondary end-point.

Results: Fifty patients entered the study with forty-three patients completing all study parts. No serious adverse events were reported. A significant up-regulation of HMGCR following atorvastatin treatment was observed in 27 of 30 patients with discordant HMGCR expression in paired samples (p = 0.0002, McNemar-Bowker test). A non-significant average decrease in proliferation (Ki67) was observed in 15 of 26 evaluable samples (relative reduction 7.6%, p = 0.39), irrespective of HMGCR expression. However, tumors with any positive HMGCR expression in pre-treatment samples had a significant decrease in Ki67 of 24% (p = 0.02). The odds of Ki67 decrease was 7.3 times higher in tumors with any HMGCR compared to tumors with absent HMGCR expression (p = 0.04, Fisher's exact test). Also the linear trend in Ki67 decreased over the four HMGCR categories (4.0% per category) and Spearman's Rho (= −0.44) were significant (p = 0.04 and p = 0.02, respectively).

Conclusions: HMGCR, the target of statin treatment, was up-regulated in breast cancer samples after atorvastatin treatment. This indicates HMGCR targeting within the tumor, which resulted in increased enzymatic activity. This study supports previous reports of statin-induced anti-proliferative effects in breast cancer, and suggests that HMGCR could be used as a predictive marker for selection of breast cancer patients with beneficial anti-tumoral effects from statin treatment.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-07.