HMG-CoAR, Premenopausal Breast Cancer and Tamoxifen Response
Introduction: We previously reported an association between tumor-specific 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) expression and a good prognosis in breast cancer. Here, the predictive value of HMG-CoAR expression in relation to tamoxifen response was examined.
Methods: HMG-CoAR protein and RNA expression was analyzed in a cell line model of tamoxifen resistance using western blotting and PCR. HMG-CoAR mRNA expression was examined in 155 tamoxifen-treated breast tumors obtained from a previously published gene expression study (Cohort I). HMG-CoAR protein expression was examined in 422 stage II premenopausal breast cancer patients, who had previously participated in a randomized control trial comparing 2 years of tamoxifen with no systemic adjuvant treatment (Cohort II). Kaplan-Meier analysis and Cox proportional hazards modeling were used to estimate the risk of recurrence-free survival (RFS) and the effect of HMG-CoAR expression on tamoxifen response.
Results: HMG-CoAR protein and RNA expression were decreased in tamoxifen-resistant MCF7-LCC9 cells compared with their tamoxifen-sensitive parental cell line. HMG-CoAR mRNA expression was decreased in tumors that recurred following tamoxifen treatment (P < 0.001) and was an independent predictor of RFS in Cohort I (hazard ratio = 0.63, P = 0.009). In Cohort II, adjuvant tamoxifen increased RFS in HMG-CoAR-positive tumors (P = 0.008). Multivariate Cox regression analysis demonstrated that HMG-CoAR was an independent predictor of improved RFS in Cohort II (hazard ratio = 0.67, P = 0.010), and subset analysis revealed that this was maintained in estrogen receptor (ER)-positive patients (hazard ratio = 0.65, P = 0.029). Multivariate interaction analysis demonstrated a difference in tamoxifen efficacy relative to HMG-CoAR expression (P = 0.05). Analysis of tamoxifen response revealed that patients with ER-positive/HMG-CoAR tumors had a significant response to tamoxifen (P = 0.010) as well as patients with ER-positive or HMG-CoAR-positive tumors (P = 0.035). Stratification according to ER and HMG-CoAR status demonstrated that ER-positive/HMG-CoAR-positive tumors had an improved RFS compared with ER-positive/HMG-CoAR-negative tumors in the treatment arm (P = 0.033); this effect was lost in the control arm (P = 0.138), however, suggesting that HMG-CoAR predicts tamoxifen response.
Conclusions: HMG-CoAR expression is a predictor of response to tamoxifen in both ER-positive and ER-negative disease. Premenopausal patients with tumors that express ER or HMG-CoAR respond to adjuvant tamoxifen.
3-Hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) acts as a rate-limiting enzyme in the mevalonate pathway. The main product of the mevalonate pathway is cholesterol; however, the pathway also produces a number of nonsterol isoprenoid side products, which are important regulators of angiogenesis, proliferation, and migration. HMG-CoAR inhibitors (statins) have demonstrated anti-neoplastic effects in vitro and in xenograft models. Statins have been suggested to lower the cancer incidence, but to date epidemiological studies have failed to confirm an association between statin use and overall breast cancer risk. A lower incidence of estrogen receptor (ER)-negative tumors has, however, been reported among statin users. Furthermore, an inverse relationship between postdiagnosis statin use and breast cancer recurrence has been reported.
We previously demonstrated an association between tumor-specific HMG-CoAR expression and improved prognosis in both breast cancer and epithelial ovarian cancer. Using immunohistochemistry in 511 incident breast cancer cases within the population-based prospective cohort Malmö Diet and Cancer Study, we demonstrated that increased levels of HMG-CoAR protein expression were associated with favorable characteristics such as a smaller tumor size, low histological grade and ER positivity. A validation study confirmed these findings and demonstrated that HMG-CoAR was an independent prognostic marker, associated with an improved recurrence-free survival (RFS) that was particularly evident in ER-positive tumors.
Based on these findings we sought to investigate the predictive value HMG-CoAR expression in tamoxifen-treated breast cancer patients. The relationship between HMG-CoAR expression and tamoxifen response was initially examined in vitro using a cell line model of tamoxifen resistance. HMG-CoAR mRNA expression was then examined in a gene expression dataset published by Chanrion and colleagues containing 155 primary breast tumors obtained from patients treated with 5 years of adjuvant tamoxifen. Finally HMG-CoAR protein expression was examined in premenopausal patients with stage II (pT2 N0 M0, pT1-2 N1 M0) invasive breast cancer. These patients had participated in a prospective randomized trial for 2 years of adjuvant tamoxifen versus no systemic treatment.
Abstract and Introduction
Abstract
Introduction: We previously reported an association between tumor-specific 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) expression and a good prognosis in breast cancer. Here, the predictive value of HMG-CoAR expression in relation to tamoxifen response was examined.
Methods: HMG-CoAR protein and RNA expression was analyzed in a cell line model of tamoxifen resistance using western blotting and PCR. HMG-CoAR mRNA expression was examined in 155 tamoxifen-treated breast tumors obtained from a previously published gene expression study (Cohort I). HMG-CoAR protein expression was examined in 422 stage II premenopausal breast cancer patients, who had previously participated in a randomized control trial comparing 2 years of tamoxifen with no systemic adjuvant treatment (Cohort II). Kaplan-Meier analysis and Cox proportional hazards modeling were used to estimate the risk of recurrence-free survival (RFS) and the effect of HMG-CoAR expression on tamoxifen response.
Results: HMG-CoAR protein and RNA expression were decreased in tamoxifen-resistant MCF7-LCC9 cells compared with their tamoxifen-sensitive parental cell line. HMG-CoAR mRNA expression was decreased in tumors that recurred following tamoxifen treatment (P < 0.001) and was an independent predictor of RFS in Cohort I (hazard ratio = 0.63, P = 0.009). In Cohort II, adjuvant tamoxifen increased RFS in HMG-CoAR-positive tumors (P = 0.008). Multivariate Cox regression analysis demonstrated that HMG-CoAR was an independent predictor of improved RFS in Cohort II (hazard ratio = 0.67, P = 0.010), and subset analysis revealed that this was maintained in estrogen receptor (ER)-positive patients (hazard ratio = 0.65, P = 0.029). Multivariate interaction analysis demonstrated a difference in tamoxifen efficacy relative to HMG-CoAR expression (P = 0.05). Analysis of tamoxifen response revealed that patients with ER-positive/HMG-CoAR tumors had a significant response to tamoxifen (P = 0.010) as well as patients with ER-positive or HMG-CoAR-positive tumors (P = 0.035). Stratification according to ER and HMG-CoAR status demonstrated that ER-positive/HMG-CoAR-positive tumors had an improved RFS compared with ER-positive/HMG-CoAR-negative tumors in the treatment arm (P = 0.033); this effect was lost in the control arm (P = 0.138), however, suggesting that HMG-CoAR predicts tamoxifen response.
Conclusions: HMG-CoAR expression is a predictor of response to tamoxifen in both ER-positive and ER-negative disease. Premenopausal patients with tumors that express ER or HMG-CoAR respond to adjuvant tamoxifen.
Introduction
3-Hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) acts as a rate-limiting enzyme in the mevalonate pathway. The main product of the mevalonate pathway is cholesterol; however, the pathway also produces a number of nonsterol isoprenoid side products, which are important regulators of angiogenesis, proliferation, and migration. HMG-CoAR inhibitors (statins) have demonstrated anti-neoplastic effects in vitro and in xenograft models. Statins have been suggested to lower the cancer incidence, but to date epidemiological studies have failed to confirm an association between statin use and overall breast cancer risk. A lower incidence of estrogen receptor (ER)-negative tumors has, however, been reported among statin users. Furthermore, an inverse relationship between postdiagnosis statin use and breast cancer recurrence has been reported.
We previously demonstrated an association between tumor-specific HMG-CoAR expression and improved prognosis in both breast cancer and epithelial ovarian cancer. Using immunohistochemistry in 511 incident breast cancer cases within the population-based prospective cohort Malmö Diet and Cancer Study, we demonstrated that increased levels of HMG-CoAR protein expression were associated with favorable characteristics such as a smaller tumor size, low histological grade and ER positivity. A validation study confirmed these findings and demonstrated that HMG-CoAR was an independent prognostic marker, associated with an improved recurrence-free survival (RFS) that was particularly evident in ER-positive tumors.
Based on these findings we sought to investigate the predictive value HMG-CoAR expression in tamoxifen-treated breast cancer patients. The relationship between HMG-CoAR expression and tamoxifen response was initially examined in vitro using a cell line model of tamoxifen resistance. HMG-CoAR mRNA expression was then examined in a gene expression dataset published by Chanrion and colleagues containing 155 primary breast tumors obtained from patients treated with 5 years of adjuvant tamoxifen. Finally HMG-CoAR protein expression was examined in premenopausal patients with stage II (pT2 N0 M0, pT1-2 N1 M0) invasive breast cancer. These patients had participated in a prospective randomized trial for 2 years of adjuvant tamoxifen versus no systemic treatment.