Citations

Abstract The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05–1.15; P = 3.49 × 10−5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13–1.31; P = 2.22 × 10−7). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89–1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18–1.33; P = 3.31 × 10−13]. Thus, 19p13.1 is the first triple-negative–specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. Cancer Res; 72(7); 1795–803. ©2012 AACR.

Abstract Percent mammographic breast density (PMD) is a strong heritable risk factor for breast cancer. However, the pathways through which this risk is mediated are still unclear. To explore whether PMD and breast cancer have a shared genetic basis, we identified genetic variants most strongly associated with PMD in a published meta-analysis of five genome-wide association studies (GWAS) and used these to construct risk scores for 3,628 breast cancer cases and 5,190 controls from the UK2 GWAS of breast cancer. The signed per-allele effect estimates of single-nucleotide polymorphisms (SNP) were multiplied with the respective allele counts in the individual and summed over all SNPs to derive the risk score for an individual. These scores were included as the exposure variable in a logistic regression model with breast cancer case–control status as the outcome. This analysis was repeated using 10 different cutoff points for the most significant density SNPs (1%–10% representing 5,222–50,899 SNPs). Permutation analysis was also conducted across all 10 cutoff points. The association between risk score and breast cancer was significant for all cutoff points from 3% to 10% of top density SNPs, being most significant for the 6% (2-sided P = 0.002) to 10% (P = 0.001) cutoff points (overall permutation P = 0.003). Women in the top 10% of the risk score distribution had a 31% increased risk of breast cancer [OR = 1.31; 95% confidence interval (CI), 1.08–1.59] compared with women in the bottom 10%. Together, our results show that PMD and breast cancer have a shared genetic basis that is mediated through a large number of common variants. Cancer Res; 72(6); 1478–84. ©2012 AACR.

Background and Purpose —By official, mostly unvalidated statistics, mortality from subarachnoid hemorrhage (SAH) show large variations between countries. Using uniform criteria for case ascertainment and diagnosis, a multinational comparison of attack rates and case fatality rates of SAH has been performed within the framework of the WHO MONICA Project. Methods —In 25- to 64-year-old men and women, a total of 3368 SAH events were recorded during 35.9 million person-years of observation in 11 populations in Europe and China. Strict MONICA criteria were used for case ascertainment and diagnosis of stroke subtype. Case fatality was based on follow-up at 28 days after onset. Results —Age-adjusted average annual SAH attack rates varied 10-fold among the 11 populations studied, from 2.0 (95% CI 1.6 to 2.4) per 100 000 population per year in China-Beijing to 22.5 (95% CI 20.9 to 24.1) per 100 000 population per year in Finland. No consistent pattern was observed in the sex ratio of attack rates in the different populations. The overall 28-day case fatality rate was 42%, with 2-fold differences in age-adjusted rates between populations but little difference between men and women. Case fatality rates were consistently higher in Eastern than in Western Europe. Conclusions —Using a uniform methodology, the WHO MONICA Project has shown very large variations in attack rates of SAH across 11 populations in Europe and China. The generally accepted view that women have a higher risk of SAH than men does not apply to all populations. Marked differences in outcome of SAH add to the wide gap in the burden of stroke between East and West Europe.

Abstract MN Background: Breast cancer is the second leading cause of cancer death of women worldwide. One of the major challenges for a better prognosis of breast cancer patients is the ineffectiveness of chemotherapy and drug resistance. To investigate the mechanisms of drug resistance, resistant cancer cell lines have been established with various anticancer agents. We found that FASN, an important metabolic enzyme overexpressed in aggressive carcinomas, is t responsible in part for the drug resistance phenotype of breast cancer cells. Our findings show that blockage of FASN augments the cytotoxicity of the anti-mitotic drug Taxol in breast cancer cells. Moreover, C75 and Taxol have a synergistic effect both drugs are combined. The in vivo effect of C75 and Taxol and the mechanism by which blockage of FASN sensitizes the cells to chemotherapy are unknown. Material and Methods: In this study first we show the effect of C75 plus Taxol in breast tumor growth. BT474 cells were injected into the mammary fat pad of nude mice to generate the tumors. When the tumors were measurable we treated the mice with C75, Taxol or with a combination of both drugs. Second we studied the lipid rafts disruption after treatments by sucrose gradient and immunofluorescence. Results: We found that C75 plus Taxol extensively inhibited the tumor growth 9 fold and reduced the tumor size in 4 fold comparedn to the control mice (no treatement). In comparison C75 alone reduced the tumor growth in 1.5 fold only; and Taxol 2.5 fold compared to the control mice. These results show for first time that blockage of FASN (with C75) sensitizes breast cancer tumors to Taxol treatment in vivo. In addition, we studied the possible mechanism involved in the sensitization of breast cancer cells to Taxol by FASN blockage. Previous studies reported that blockage of FASN or Taxol treatment decrease the sphingolipids synthesis. Sphingolipids and cholesterol are the most abundant fatty acid in the lipid rafts in the plasma membrane. Disruption of lipid rafts has been shown to induce apoptosis in different carcinoma cell lines. Based in these findings, we studied lipid rafts in BT474 cells treated with C75, Taxol or combination of both with sucrose gradient and immunofluorescence microscopy. Discussion: Our results show that C75 and Taxol disrupt the lipid rafts. Thesefindings show that FASN is a new mechanism of drug resistance and may be an ideal target for chemosensitization in breast cancer chemotherapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-03-01.

AbstractCCN1, also known as CYR61, is a survival and proangiogenic factor overexpressed in about 30% of invasive breast carcinomas, and particularly in triple-negative breast carcinomas (TNBC). CCN1 expression in breast cancer promotes tumorigenicity, metastasis, antihormone, and chemoresistance. TNBCs often develop bone metastasis, thus the vast majority of patients receive bisphosphonate treatment as a companion to chemotherapy. Zoledronic acid (ZOL), a bisphosphonate currently in use, inhibits bone resorption, prevents development of new osteolytic lesions induced by tumor metastasis, and has a direct antitumor activity in breast cancer cells and tumors. We have shown that ZOL inhibits anchorage independent growth as well as branching and morphogenesis in CCN1 overexpressing cells. However, the mechanism is not yet well understood. In this study, we investigate the effect of ZOL in breast cancer cells with high and undetectable CCN1 expression levels. We show that CCN1-expressing cells are more sensitive to ZOL, that ZOL induces downregulation of the CCN1 promoter activity and CCN1 protein expression in a dose-dependent manner, and that ZOL is associated with a decrease in phosphorylated Akt and translocation of FOXO3a, a negative regulator of CCN1 expression, to the nucleus. Deletion of the FOXO3a binding site in the CCN1 promoter prevents ZOL inhibition of the CCN1 promoter activity showing that FOXO3a transcriptional activation is necessary for ZOL to induce CCN1 inhibition. This study provides evidence that ZOL targets the proangiogenic factor (CCN1) through FOXO3a and reveals a new mechanism of ZOL action in breast cancer cells. Mol Cancer Ther; 10(5); 732–41. ©2011 AACR.