SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer.

In this study, we report the identification of a novel role of SIRT6 in both epirubicin and paclitaxel resistance in breast cancer. We found that SIRT6 protein levels are elevated in paclitaxel- and epirubicin-resistant MCF-7 cells compared with the parental sensitive cells. SIRT6 knockout and depletion sensitized cells to both paclitaxel and epirubicin treatment, whereas SIRT6 ectopic overexpression led to increased resistance to paclitaxel and epirubicin. Moreover, our data suggest that SIRT6 could be mediating epirubicin resistance through enhancing the DNA repair response to epirubicin-induced DNA damage. Clonogenic assays also revealed that mouse embryonic fibroblasts (MEFs) lacking SIRT6 have decreased long-term viability in response to epirubicin. The tumour suppressor FOXO3a increases its levels of acetylation in MEFs depleted of SIRT6, whereas its induction by epirubicin is attenuated in breast cancer cells overexpressing SIRT6. Further cell viability studies demonstrate that deletion of FOXO1/3/4 in MEFs can confer sensitivity to both paclitaxel and epirubicin, suggesting that SIRT6 reduces paclitaxel and epirubicin sensitivity, at least in part, through modulating FOXO acetylation and expression. Consistently, immunohistochemical analysis of 118 breast cancer patient samples revealed that high SIRT6 nuclear staining is significantly associated with poorer overall survival (P = 0.018; Kaplan-Meier analysis). Multivariate Cox analysis demonstrated that nuclear SIRT6 staining remained associated with death after correcting for tumour stage and lymph-node involvement (P = 0.033). Collectively, our data suggest that SIRT6 has a role in paclitaxel and epirubicin sensitivity via targeting FOXO proteins and that SIRT6 could be a useful biomarker and therapeutic target for paclitaxel- and epirubicin-resistant cancer.

Optimizing resource allocation for breast cancer prevention and care among Hong Kong Chinese women.

BACKGROUND: Recommendations about funding of interventions through the full spectrum of the disease often have been made in isolation. The authors of this report optimized budgetary allocations by comparing cost-effectiveness data for different preventive and management strategies throughout the disease course for breast cancer in Hong Kong (HK) Chinese women. METHODS: Nesting a state-transition Markov model within a generalized cost-effectiveness analytic framework, costs and quality-adjusted life-years (QALYs) were compared to estimate average cost-effectiveness ratios for the following interventions at the population level: biennial mass mammography (ages 40-69 years or ages 40-79 years), reduced waiting time for postoperative radiotherapy (by 15% or by 25%), adjuvant endocrine therapy (either upfront aromatase inhibitor [AI] therapy or sequentially with tamoxifen followed by AI) in postmenopausal women with estrogen receptor-positive disease, targeted immunotherapy in those with tumors that over express human epidermal growth factor receptor 2, and enhanced palliative services (either at home or as an inpatient). Usual care for eligible patients in the public sector was the comparator. RESULTS: In descending order, the optimal allocation of additional resources for breast cancer would be the following: a 25% reduction in waiting time for postoperative radiotherapy (in US dollars: $5000 per QALY); enhanced, home-based palliative care ($7105 per QALY); adjuvant, sequential endocrine therapy ($17,963 per QALY); targeted immunotherapy ($62,092 per QALY); and mass mammography screening of women ages 40 to 69 years ($72,576 per QALY). CONCLUSIONS: Given the lower disease risk and different age profiles of patients in HK Chinese, among other newly emergent and emerging economies with similar transitioning epidemiologic profiles, the current findings provided direct evidence to support policy decisions that may be dissimilar to current Western practice.

SpliceArray profiling of breast cancer reveals a novel variant of NCOR2/SMRT that is associated with tamoxifen resistance and control of ERα transcriptional activity.

Gene expression profiling aimed at classifying and prognosing breast cancer has yielded signatures with little, if any, concordance. However, expression arrays used in these studies do not discriminate alternate RNA splice isoforms that vary widely in cancer and may resolve this problem. In this study, we profiled splice isoforms in a panel of tamoxifen-sensitive and -resistant cell lines, defining a novel variant (BQ323636.1) of the nuclear receptor corepressor 2 (NCOR2) that was associated with tamoxifen resistance. Overexpression of this variant in a tamoxifen-sensitive cell line induced its resistance to tamoxifen. We confirmed our initial findings from cell lines in 77 breast tumors from a Chinese cohort, where BQ323636.1 expression was higher in tamoxifen-resistant patients than tamoxifen-sensitive patients. For patients who were estrogen receptor (ER)-positive and had received tamoxifen treatment, higher BQ323636.1 expression level correlated with distant metastasis. High expression level of BQ323636.1 was found to be associated with poorer overall and disease-free survival for patients who had received tamoxifen treatment. Notably, higher BQ323636.1 versus NCOR2 wild-type ratio was also associated with negative ER and progesterone receptor (PR) status, and triple-negative status (ER-/PR-/HER2- receptor status). Mechanistic investigations showed that under conditions of tamoxifen exposure, BQ323636.1 suppressed the transcriptional activity of ERα, exhibiting promoter-regulating functions. Our findings highlight a novel splice variant of the ERα corepressor NCOR2 as a candidate biomarker in breast cancer that not only predicts tamoxifen response but may be targeted to overcome tamoxifen resistance.

Association of exon 19 and 21 EGFR mutation patterns with treatment outcome after first-line tyrosine kinase inhibitor in metastatic non-small-cell lung cancer.

BACKGROUND: This study investigated whether there were differential survival outcomes to first-line tyrosine kinase inhibitors (TKI) in patients with metastatic non-small-cell lung cancer harboring different subtypes of exon 19 and exon 21 mutations on epidermal growth factor receptor (EGFR). METHODS: Of 452 patients with stage IIIB and IV non-small-cell lung cancer, 192 patients (42.5%) harbored EGFR mutation and 170 (37.5%) received TKI as first-line treatment. EGFR mutation analysis was performed by direct sequencing. Survival and response outcome were compared among different subtypes of exon 19 and exon 21 EGFR mutations in these 170 patients. RESULTS: Patients harboring exon 19 18-nucleotide deletion (delL747_P753insS) had the shortest median progression-free survival (PFS) (6.5 months), followed by those with 15-nucleotide deletion (delE746_A750) (12.4 months) and mixed insertion/substitution mutations (22.3 months; p = 0.012). However, patients who had exon 19 deletions starting on codon E746 had better median PFS (14.2 months) than those starting on L747 (6.5 months; hazard ratio, 0.445; 95% confidence interval [0.219-0.903]; p = 0.021). Besides, exon 21 L858R derived a longer median PFS than L861R/L861Q (11.4 months versus 2.1 months, respectively; hazard ratio, 0.298; 95% confidence interval [0.090-0.980]; p = 0.034). CONCLUSIONS: Different subtypes of EGFR exon 19 and 21 mutations exhibited differential survival to first-line TKI therapy. Detailed sequence evaluation of exon 19 deletions may provide important prognostic information on survival outcome after TKI.