Estrogen and progesterone receptor levels in nonneoplastic breast epithelium of breast cancer cases versus benign breast biopsy controls

<p>Abstract</p> <p>Background</p> <p>Previous studies and biological mechanisms of carcinogenesis suggest that the steroid receptor content of benign breast epithelium may be related to breast cancer risk. The objective in this study was to compare the levels of estrogen receptor-α (ER) and progesterone receptor (PR) in nonneoplastic breast epithelium between breast cancer cases and biopsy controls.</p> <p>Methods</p> <p>Between 1995 and 1997 at two sites (Women's College Hospital in Toronto and Kingston General Hospital), 667 women who were scheduled for diagnostic excisional breast biopsies completed a questionnaire providing personal information and agreed to allow analysis of routinely resected tissue. Histological slides with nonneoplastic epithelium were available for 101 cancer cases and 200 biopsy controls in Toronto and for 105 cancer cases and 119 controls in Kingston. Nonneoplastic epithelium was examined with immunohistochemical assays to determine the percent of epithelial cells staining for ER and PR. Unconditional logistic regression was used to calculate odds ratios (OR) stratified by study site.</p> <p>Results</p> <p>The ER content of nonneoplastic tissue was higher in cases than biopsy controls in unadjusted analyses; after adjustment for age, however, a weak association remained in only one of the study sites. After adjustment for age, the PR content of nonneoplastic tissue was slightly lower in breast cancer cases than controls in one study site. Furthermore, this inverse association was confined to women with PR negative breast cancer in comparison to the controls. No interaction between ER and PR content of nonneoplastic tissue was observed in relation to the odds of having breast cancer.</p> <p>Conclusion</p> <p>The results of this study are consistent with only a slight indication of increased ER levels in nonneoplastic tissue in breast cancer cases relative to controls. This study contributes to the understanding of breast cancer by examining both ER and PR in nonneoplastic tissue. Limitations remain, however, such as the necessity of using as controls women with benign breast changes, difficulties in selecting the appropriate tissue for analysis, and tissue sampling concurrent to diagnosis.</p

Changes in insulin resistance indicators, IGFs, and adipokines in a year-long trial of aerobic exercise in postmenopausal women

Physical activity is a known modifiable lifestyle means for reducing postmenopausal breast cancer risk, but the biologic mechanisms are not well understood. Metabolic factors may be involved. In this study, we aimed to determine the effects of exercise on insulin resistance (IR) indicators, IGF1, and adipokines in postmenopausal women. The Alberta Physical Activity and Breast Cancer Prevention Trial was a two-armed randomized controlled trial in postmenopausal, inactive, cancer-free women. A year-long aerobic exercise intervention of 225 min/week (n=160) was compared with a control group asked to maintain usual activity levels (n=160). Baseline, 6- and 12-month serum levels of insulin, glucose, IGF1, IGF-binding protein 3 (IGFBP3), adiponectin, and leptin were assayed, and after data collection, homeostasis model assessment of IR (HOMA-IR) scores were calculated. Intention-to-treat analyses were performed using linear mixed models. The treatment effect ratio (TER) of exercisers to controls was calculated. Data were available on 308 (96.3%) women at 6 months and 310 (96.9%) women at 12 months. Across the study period, statistically significant reductions in insulin (TER=0.87, 95% confidence interval (95% CI)=0.81–0.93), HOMA-IR (TER=0.86, 95% CI=0.80–0.93), and leptin (TER=0.82, 95% CI=0.78–0.87), and an increase in the adiponectin/leptin ratio (TER=1.21, 95% CI=1.13–1.28) were observed in the exercise group compared with the control group. No significant differences were observed for glucose, IGF1, IGFBP3, adiponectin or the IGF1/IGFBP3 ratio. Previously inactive postmenopausal women who engaged in a moderate-to-vigorous intensity exercise program experienced changes in insulin, HOMA-IR, leptin, and adiponectin/leptin that might decrease the risk for postmenopausal breast cancer

Novel Associations between Common Breast Cancer Susceptibility Variants and Risk-Predicting Mammographic Density Measures.

Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk, but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute nondense area adjusted for study, age, and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210 (ESR1), and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all P < 10(-5)). Of 41 recently discovered breast cancer susceptibility variants, associations were found between rs1432679 (EBF1), rs17817449 (MIR1972-2: FTO), rs12710696 (2p24.1), and rs3757318 (ESR1) and adjusted absolute and percent dense areas, respectively. There were associations between rs6001930 (MKL1) and both adjusted absolute dense and nondense areas, and between rs17356907 (NTN4) and adjusted absolute nondense area. Trends in all but two associations were consistent with those for breast cancer risk. Results suggested that 18% of breast cancer susceptibility variants were associated with at least one mammographic density measure. Genetic variants at multiple loci were associated with both breast cancer risk and the mammographic density measures. Further understanding of the underlying mechanisms at these loci could help identify etiologic pathways implicated in how mammographic density predicts breast cancer risk.ABCFS: The Australian Breast Cancer Family Registry (ABCFR; 1992-1995) was supported by the Australian NHMRC, the New South Wales Cancer Council, and the Victorian Health Promotion Foundation (Australia), and by grant UM1CA164920 from the USA National Cancer Institute. The Genetic Epidemiology Laboratory at the University of Melbourne has also received generous support from Mr B. Hovey and Dr and Mrs R.W. Brown to whom we are most grateful. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Breast Cancer Susceptibility Variants and Mammographic Density 5 Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. BBCC: This study was funded in part by the ELAN-Program of the University Hospital Erlangen; Katharina Heusinger was funded by the ELAN program of the University Hospital Erlangen. BBCC was supported in part by the ELAN program of the Medical Faculty, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg. EPIC-Norfolk: This study was funded by research programme grant funding from Cancer Research UK and the Medical Research Council with additional support from the Stroke Association, British Heart Foundation, Department of Health, Research into Ageing and Academy of Medical Sciences. MCBCS: This study was supported by Public Health Service Grants P50 CA 116201, R01 CA 128931, R01 CA 128931-S01, R01 CA 122340, CCSG P30 CA15083, from the National Cancer Institute, National Institutes of Health, and Department of Health and Human Services. MCCS: Melissa C. Southey is a National Health and Medical Research Council Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. The study was supported by the Cancer Council of Victoria and by the Victorian Breast Cancer Research Consortium. MEC: National Cancer Institute: R37CA054281, R01CA063464, R01CA085265, R25CA090956, R01CA132839. MMHS: This work was supported by grants from the National Cancer Institute, National Institutes of Health, and Department of Health and Human Services. (R01 CA128931, R01 CA 128931-S01, R01 CA97396, P50 CA116201, and Cancer Center Support Grant P30 CA15083). Breast Cancer Susceptibility Variants and Mammographic Density 6 NBCS: This study has been supported with grants from Norwegian Research Council (#183621/S10 and #175240/S10), The Norwegian Cancer Society (PK80108002, PK60287003), and The Radium Hospital Foundation as well as S-02036 from South Eastern Norway Regional Health Authority. NHS: This study was supported by Public Health Service Grants CA131332, CA087969, CA089393, CA049449, CA98233, CA128931, CA 116201, CA 122340 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. OOA study was supported by CA122822 and X01 HG005954 from the NIH; Breast Cancer Research Fund; Elizabeth C. Crosby Research Award, Gladys E. Davis Endowed Fund, and the Office of the Vice President for Research at the University of Michigan. Genotyping services for the OOA study were provided by the Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096. OFBCR: This work was supported by grant UM1 CA164920 from the USA National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. SASBAC: The SASBAC study was supported by Märit and Hans Rausing’s Initiative against Breast Cancer, National Institutes of Health, Susan Komen Foundation and Agency for Science, Technology and Research of Singapore (A*STAR). Breast Cancer Susceptibility Variants and Mammographic Density 7 SIBS: SIBS was supported by program grant C1287/A10118 and project grants from Cancer Research UK (grant numbers C1287/8459). COGS grant: Collaborative Oncological Gene-environment Study (COGS) that enabled the genotyping for this study. Funding for the BCAC component is provided by grants from the EU FP7 programme (COGS) and from Cancer Research UK. Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692), the National Institutes of Health (CA128978) and Post- Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAMEON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund.This is the author accepted manuscript. The final version is available via American Association for Cancer Research at http://cancerres.aacrjournals.org/content/early/2015/04/10/0008-5472.CAN-14-2012.abstract

Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression.

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.ajhg.2015.05.002

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.352

Adiposity and mammographic density

Bibliography: p. 201-233Some pages are in colour

The relation of leptin and adiponectin with breast density among premenopausal women.

The adipocytokine leptin may increase breast cancer risk, while adiponectin may be protective. We examined the association of the two circulating markers with mammographic density, a strong predictor of breast cancer risk. For 183 premenopausal participants of a nutritional trial, mammograms performed at baseline, year 1 and year 2 were assessed for density using a computer-assisted method. Serum samples obtained at the same time were analyzed for leptin and adiponectin by enzyme-linked immunosorbent assay. We applied mixed models to incorporate the repeated measurements while adjusting for confounders including body mass index (BMI). At baseline, the mean age of the participants was 42.6+/-2.9 years; 40% were of Asian ancestry. Leptin was lower and adiponectin higher in normal weight than overweight women. Neither marker was related to absolute breast density. The significant inverse association of leptin with percent density disappeared when BMI was added to the model. After stratification by weight, percent density decreased with higher leptin levels in normal weight women, whereas it increased among overweight participants. After adjustment for BMI, the positive association between percent density and adiponectin was greatly reduced and no longer significant. These results do not support a strong association of leptin or adiponectin with breast cancer risk as assessed by mammographic density. In contrast, the findings suggest the possibility that the inverse association of BMI with breast cancer risk in premenopausal women is mediated by adipocytokines

Classification of individual pain response trajectories following medically indicated heel lances in preterm infants during their NICU admission

Objectives: infants born preterm are exposed to repeated painful procedures during neonatal intensive care unit admission. Particularly in preterm infants, trajectories of pain response are not well understood. The aim of this study was to classify pain response trajectories over 2 minute following medically indicated heel lances in preterm infants.Materials and methods: this study used existing clinical trial data (NCT01561547) that evaluated the efficacy of kangaroo care and sucrose for infant pain control. Pain was measured using the Premature Infant Pain Profile at 30, 60, 90, and 120 seconds following a heel lance. Group-based trajectory modeling was used to classify pain response in this 2 minute period.Results: a total of 236 infants with median gestational age of 33 weeks contributed 610 procedures. A model with 5 trajectory classes best fit the data. Three trajectories were stable over time at different levels of intensity from low-mild to low-moderate pain. One trajectory reflected a linear reduction from high-moderate to low-moderate pain. The final trajectory showed variable moderate-high pain. At all times points, 3 classes were at least 1-point different from the overall sample mean pain score. Only 21 (9%) infants maintained the same class for all 3 procedures.Discussion: in this sample of preterm infants receiving pain relief, most pain trajectories reflected mild to low-moderate pain that was stable over 2 minute after heel lance initiation. Trajectories were not consistent over multiple procedures within infants, and an overall mean pain score for the sample may misrepresent subgroups of pain response.</p