Kerryn W. Reding

Genetic polymorphisms in the catechol estrogen metabolism pathway and breast cancer risk.

Background: This study investigated whether single nucleotide polymorphisms (SNP) in genes within the catechol estrogen metabolism pathway altered the risk of breast cancer alone or in combination, as well as whether menopausal hormone therapy modified the effect of these SNPs on breast cancer risk. Methods: In a population-based case-control study of breast cancer, 891 cases and 878 controls were genotyped for six functional SNPs in the COMT, CYP1B1, GSTM1, GSTP1, and GSTT1 genes. Results: Women homozygous with the T allele in CYP1B1*2 (Ser119; rs1056827) were at 1.69 (95% confidence interval, 1.17-2.46) times the risk of women homozygous with the G allele; women homozygous with the G allele in GSTP1 (Val105; rs1695) were at 0.73 (95% confidence interval, 0.54-0.99) times the risk of breast cancer compared with women homozygous with the A allele. No other SNPs tested were associated with breast cancer to any appreciable degree. Potential gene-gene and gene-hormone therapy interactions were investigated. Conclusion: With the exception of GSTP1 and possibly CYP1B1*2, our findings do not provide support for the role of genetic variation in the catechol estrogen metabolism pathway and breast cancer risk in postmenopausal women. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1461–7)

Effect of Prediagnostic Alcohol Consumption on Survival after Breast Cancer in Young Women

Background: Alcohol consumption has been comprehensively investigated as an etiologic risk factor for breast cancer but has received little attention in terms of its effect on prognosis after breast cancer, particularly for young women. Methods: 1,286 women diagnosed with invasive breast cancer at age ≤45 years from two population-based case-control studies in the Seattle-Puget Sound region were followed from their diagnosis of breast cancer (between January 1983 and December 1992) for survival through June 2002, during which time 364 women had died. Cox proportional hazards modeling was used to assess the effect of prediagnostic alcohol consumption on the risk of dying. Results: After adjusting for age and diagnosis year, compared with nondrinkers, women who consumed alcohol in the 5 years before diagnosis had a decreased risk of death [>0 to <3 drinks per week: hazard ratio, 0.7; 95% confidence interval (95% CI), 0.6-0.95; 3 to <7 drinks per week: risk ratio, 0.6; 95% CI, 0.4-0.8;7 drinks per week: risk ratio, 0.7; 95% CI, 0.5-0.9]. This association was unchanged on additional adjustment for potential confounders including most notably treatment, stage at diagnosis, and mammogram history. Conclusion: These results suggest that women who consume alcohol before a diagnosis of breast cancer have improved survival, which does not appear to be attributable to differences in stage, screening, or treatment. (Cancer Epidemiol Biomarkers Prev 2008;17(8):1988–96)

Relationship between Patterns of Alcohol Consumption and Gastrointestinal Symptoms among Patients with Irritable Bowel Syndrome

OBJECTIVES:Heavy alcohol intake may exacerbate gastrointestinal (GI) symptoms in adults with irritable bowel syndrome (IBS); however, the role of alcohol in IBS is unclear. We investigated prospective associations between daily patterns of alcohol intake and next days GI symptoms using daily diaries.METHODS:In an observational study of women aged 18–48 years with IBS and healthy controls, participants recorded daily GI symptoms, alcohol intake, caffeine intake, and cigarette smoking for ∼1 month. GI symptoms included abdominal pain, abdominal bloating, intestinal gas, diarrhea, constipation, nausea, stomach pain, heartburn, and indigestion. Binge drinking was defined as 4+ alcohol-containing drinks/day.RESULTS:Patterns of alcohol intake did not differ between IBS patients and controls. Although patterns of drinking were associated with GI symptoms among women with IBS, this was not the case with the healthy controls. The strongest associations for IBS patients were between binge drinking and the next days GI symptoms (e.g., diarrhea, P=0.006; nausea, P=0.01; stomach pain, P=0.009; and indigestion, P=0.004), whereas moderate and light drinking either were not associated or weakly associated with GI symptoms. Associations between alcohol intake and GI symptoms were stronger for women with IBS-diarrhea than for IBS-constipation or IBS-mixed. Effects of binge drinking on GI symptoms were strongest when comparing between individuals (rather than within individuals).CONCLUSIONS:Our findings indicate that IBS symptoms differ according to the pattern of alcohol intake among IBS patients, suggesting that the pattern of drinking may in part explain the inconsistent findings between alcohol and IBS symptoms.

Associations of insulin-like growth factor and insulin-like growth factor binding protein-3 with mortality in women with breast cancer

Elevated circulating insulin‐like growth factor‐1 (IGF‐1), a breast epithelial cell mitogen, is associated with breast cancer development. However, its association with breast cancer survival is not established. Circulating concentrations of IGF‐1 are controlled via binding proteins, including IGF Binding Protein‐3 (IGFBP‐3), that may modulate the association of IGF‐1 with breast‐cancer outcomes. We measured IGF‐1 and IGFBP‐3 concentrations in serum from 600 women enrolled in the health, eating, activity, and lifestyle (HEAL) study, a multiethnic, prospective cohort study of women diagnosed with stage I‐IIIA breast cancer. We evaluated the association between IGF‐1 and IGFBP‐3, and as a ratio, modeled using quintile cut‐points, with risk of breast cancer‐specific (n = 42 deaths) and all‐cause mortality (n = 87 deaths) using Cox proportional hazards models. In models adjusted for body mass index, ethnicity, tamoxifen use at time of blood draw, treatment received at diagnosis and IGFBP‐3, women in the highest quintile of IGF‐1 level had an increased risk of all‐cause mortality (Hazard Ratio (HR) = 3.10, 95% CI 1.21–7.93, p = 0.02), although no dose‐response association was evident. The IGF‐1/IGFBP‐3 ratio, an indicator of free IGF‐I levels, was significantly associated with increasing risk of all‐cause mortality (HR = 2.83, 95% CI 1.25–6.36 ptrend = 0.01, upper vs. lower quintile) in a fully adjusted model. In conclusion, high serum levels of IGF‐1 and the IGF‐1/IGFBP‐3 ratio were associated with increased risk of all‐cause mortality in women with breast cancer. These results need to be confirmed in larger breast cancer survivor cohorts.

Immobilized Metal Affinity Chromatography Coupled to Multiple Reaction Monitoring Enables Reproducible Quantification of Phospho-signaling

A major goal in cell signaling research is the quantification of phosphorylation pharmacodynamics following perturbations. Traditional methods of studying cellular phospho-signaling measure one analyte at a time with poor standardization, rendering them inadequate for interrogating network biology and contributing to the irreproducibility of preclinical research. In this study, we test the feasibility of circumventing these issues by coupling immobilized metal affinity chromatography (IMAC)-based enrichment of phosphopeptides with targeted, multiple reaction monitoring (MRM) mass spectrometry to achieve precise, specific, standardized, multiplex quantification of phospho-signaling responses. A multiplex immobilized metal affinity chromatography- multiple reaction monitoring assay targeting phospho-analytes responsive to DNA damage was configured, analytically characterized, and deployed to generate phospho-pharmacodynamic curves from primary and immortalized human cells experiencing genotoxic stress. The multiplexed assays demonstrated linear ranges of ≥3 orders of magnitude, median lower limit of quantification of 0.64 fmol on column, median intra-assay variability of 9.3%, median inter-assay variability of 12.7%, and median total CV of 16.0%. The multiplex immobilized metal affinity chromatography- multiple reaction monitoring assay enabled robust quantification of 107 DNA damage-responsive phosphosites from human cells following DNA damage. The assays have been made publicly available as a resource to the community. The approach is generally applicable, enabling wide interrogation of signaling networks.

Breast Cancer Risk in Relation to Ambient Air Pollution Exposure at Residences in the Sister Study Cohort

Background: Some but not all past studies reported associations between components of air pollution and breast cancer, namely fine particulate matter ≤2.5 μm (PM2.5) and nitrogen dioxide (NO2). It is yet unclear whether risks differ according to estrogen receptor (ER) and progesterone receptor (PR) status. Methods: This analysis includes 47,591 women from the Sister Study cohort enrolled from August 2003 to July 2009, in whom 1,749 invasive breast cancer cases arose from enrollment to January 2013. Using Cox proportional hazards and polytomous logistic regression, we estimated breast cancer risk associated with residential exposure to NO2, PM2.5, and PM10. Results: Although breast cancer risk overall was not associated with PM2.5 [HR = 1.03; 95% confidence intervals (CI), 0.96–1.11], PM10 (HR = 0.99; 95% CI, 0.98–1.00), or NO2 (HR = 1.02; 95% CI, 0.97–1.07), the association with NO2 differed according to ER/PR subtype (P = 0.04). For an interquartile range (IQR) difference of 5.8 parts per billion (ppb) in NO2, the relative risk (RR) of ER+/PR+ breast cancer was 1.10 (95% CI, 1.02–1.19), while there was no evidence of association with ER−/PR− (RR = 0.92; 95% CI, 0.77–1.09; Pinteraction = 0.04). Conclusions: Within the Sister Study cohort, we found no significant associations between air pollution and breast cancer risk overall. But we observed an increased risk of ER+/PR+ breast cancer associated with NO2. Impact: Though these results suggest there is no substantial increased risk for breast cancer overall in relation to air pollution, NO2, a marker of traffic-related air pollution, may differentially affect ER+/PR+ breast cancer. Cancer Epidemiol Biomarkers Prev; 24(12); 1907–9. ©2015 AACR.

A 12-month moderate-intensity exercise intervention does not alter serum prolactin concentrations.

INTRODUCTION Many studies have investigated the immediate impact of physical activity on prolactin concentrations; however, it is currently unclear what impact exercise may have on prolactin concentrations in the long-term, particularly among women. Understanding the role of exercise on prolactin is important because epidemiologic studies have reported increased risks of breast cancer in association with high prolactin concentrations. We investigated whether exercise alters serum prolactin concentrations at two time points within a one-year exercise intervention. METHODS Out of 96 women aged 40-75 years, 47 were randomized to a 12-month regimen of moderate-intensity physical activity and 49 were randomized to the control group. Participants in the exercise group (exercisers) took part in exercise at gym facilities 3 times per week and 3 times per week on their own. Serum prolactin was collected from participants at baseline, 3 and 12 months. Using generalized linear models, we compared the percent change in prolactin concentrations from baseline to the two follow-up time points in the exercisers versus the control group. RESULTS While we observed the suggestion of differences in the change in serum prolactin concentrations in some subgroups, overall there was no difference in the change in prolactin concentrations between exercisers and controls at 3 months (p=0.57) or 12 months (p=0.42). CONCLUSION Our study does not support the hypothesis that long-term exercise influences serum prolactin concentrations.

Lifestyle factors and subsequent ischemic heart disease risk after hematopoietic cell transplantation: Lifestyle and Heart Disease After HCT

The objective of this study was to evaluate whether modifiable cardiovascular risk conditions and lifestyle factors were temporally associated with an increased risk for ischemic heart disease and overall mortality in a cohort of hematopoietic cell transplantation (HCT) survivors.

Medical advocacy among African-American women diagnosed with breast cancer: from recipient to resource.

PurposeMedical advocacy at multiple levels (self, community/interpersonal, national/public health interest) may be helpful to address the disproportionate burden of breast cancer African-American women encounter. Little, however, is known about the interplay of medical advocacy at different levels.MethodsWe analyzed qualitative data from two studies focused on the psychosocial experiences of breast cancer among 38 African-American women living in Western Washington State.ResultsEmergent themes suggested that survivors received community/interpersonal advocacy from different members of social networks in the form of social support (appraisal, emotional, informational, instrumental). Survivors indicated that receiving this support was associated with greater self-advocacy in terms of their own care experiences, as well as greater community/interpersonal advocacy on their part as resources to other women diagnosed with breast cancer, their family, friends, and larger communities.ConclusionOur findings suggest that community/interpersonal advocacy, including providing different types of support, may lead to improved self-advocacy as well as health-protective impacts for the networks in which survivors are embedded. Future quantitative research is warranted to support these findings and assess how this interplay is associated with improved outcomes among this marginalized and resilient population.

Fruit intake associated with urinary estrogen metabolites in healthy premenopausal women

Urinary concentrations of 2:16-hydroxyestrone (2:16-OHE1) approximate concentrations of 2-OHE1 and 16α -OHE1 in breast tissue. As estrogens are purported to be involved in breast cancer development, the 2:16-OHE1 ratio can provide an indication of estrogen metabolite exposure in the breast. With prior studies observing associations between urinary estrogen metabolites and dietary intake of fruits, vegetables, and fiber ascertained from food questionnaires, we examined associations between dietary factors ascertained through 3-day food records and urinary 2:16-OHE1 in 191 pre-menopausal healthy women. Fruit consumption was positively associated with 2:16-OHE1 after adjustment for total energy, ethnicity, body mass index, parity, smoking history, and serum estradiol (p= 0.003). Fruit consumption was positively associated with 2- OHE1 concentrations (p=0.006), but was not associated with 16α-OHE1 (p=0.92). The Musaceae botanical grouping (comprised primarily of bananas) was positively associated with the 2:16-OHE1 ratio, and Rosaceae (comprised of citrus fruits) and Musaceae botanical groupings were positively associated with 2-OHE1 (but not 16α-OHE1) concentrations, after adjustment for confounders. Our data suggest that dietary fruit intake is associated with urinary 2- OHE1 and the 2:16-OHE1 ratio and that breast tissue exposure to estrogen metabolites may thus be influenced by diet.