Gene-Specific Promoter Methylation Status in Hormone-Receptor-Positive Breast Cancer Associates with Postmenopausal Body Size and Recreational Physical Activity

Abstract

Introduction Breast cancer, the leading cancer diagnosis among American women, is positively associated with postmenopausal obesity and little or no recreational physical activity (RPA). However, the underlying mechanisms of these associations remain unresolved. Aberrant changes in DNA methylation may represent an early event in carcinogenesis, but few studies have investigated associations between obesity/RPA and gene methylation, particularly in postmenopausal breast tumors where these lifestyle factors are most relevant. Methods We used case-case unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the associations between body mass index (BMI=weight [kg]/height [m2]) in the year prior to diagnosis, or RPA (average hours/week), and methylation status (methylated vs. unmethylated) of 13 breast cancer-related genes in 532 postmenopausal breast tumor samples from the Long Island Breast Cancer Study Project. We also explored whether the association between BMI/RPA and estrogen/progesterone-receptor status (ER+PR+ vs. all others) was differential with respect to gene methylation status. Methylation-specific PCR and the MethyLight assay were used to assess gene methylation. Results BMI 25-29.9kg/m2, and perhaps BMI≥30kg/m2, was associated with methylated HIN1 in breast tumor tissue. Cases with BMI≥30kg/m2 were more likely to have ER+PR+ breast tumors in the presence of unmethylated ESR1 (OR=2.63, 95% CI 1.32-5.25) and women with high RPA were more likely to have ER+PR+ breast tumors with methylated GSTP1 (OR=2.33, 95% CI 0.79-6.84). Discussion While biologically plausible, our findings that BMI is associated with methylated HIN1 and BMI/RPA are associated with ER+PR+ breast tumors in the presence of unmethylated ESR1 and methylated GSTP1, respectively, warrant further investigation. Future studies would benefit from enrolling greater numbers of postmenopausal women and examining a larger panel of breast cancer–related genes.

Prediagnosis aspirin use, DNA methylation, and mortality after breast cancer: A population‐based study

“…9 BC progression is most likely a multifactorial condition involving complex interactions among genetic/epigenetic and estrogen-related and inflammation-related factors. [12][13][14][15][16] Global and tumor gene-specific aberrant Cancer November 1, 2019 DNA methylation have been associated with BC prognosis in previous reports, including our own. Epigenetic modifications involve changes in gene function but do not entail a change in DNA sequence.…”

“…10 Methylation may occur during embryogenesis, is heritable by somatic cells after cell division, 11 but also can be modified during the life course under environmental stimulation and lifestyle modulation. [12][13][14][15][16] Global and tumor gene-specific aberrant Cancer November 1, 2019 DNA methylation have been associated with BC prognosis in previous reports, including our own. [17][18][19] Aberrant DNA methylation may lead to whole-genomic instability and altered gene transcription, 15 which may further induce increased mutation rates of key genes (including COX-2) upon which that aspirin acts.…”

“…The methylation status of the remaining 10 genes was measured by using the MethyLight assay. [14][15][16]18,26,37 Assessment of Global Methylation DNA also was isolated from participant blood samples that were collected by nurse/phlebotomists from 1102 (73.1%) women with BC at the time of the baseline interview. 38 These continuous values of the 10 gene-specific methylation levels were further dichotomized with ≥4% was defined as methylated.…”

“…38 These continuous values of the 10 gene-specific methylation levels were further dichotomized with ≥4% was defined as methylated. [14][15][16]18,26,37 Assessment of Global Methylation DNA also was isolated from participant blood samples that were collected by nurse/phlebotomists from 1102 (73.1%) women with BC at the time of the baseline interview. 22,26 Approximately two-thirds of the samples were obtained before chemotherapy.…”

Dietary fat and obesity as modulators of breast cancer risk: Focus on DNA methylation

“…Increased BMI has also shown a positive association with hypermethylation of both RASSF1A and BRCA1 in surgically excised breast tumours ( n = 120; Naushad et al, ). Studies have also identified that obesity was associated with hypermethylation of hairpin‐induced 1 ( HIN1 ) in post‐menopausal breast tumour tissue ( n = 532) from the Long Island BC Study Project (McCullough et al, ). The HIN1 gene encodes a protein that is a negative regulator of both cell growth and invasion (Krop, Parker, Qimron, Porter, & Polyak, ).…”