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Background: Obesity fosters worse clinical outcomes in both premenopausal and postmenopausal women with breast cancer. Emerging evidence suggests that an android body fat distribution in particular is deleterious for breast cancer prognosis. The extent of adipose tissue dysfunction, especially how it relates to breast cancer prognostic factors and anthropometric measurements, has not been fully investigated., Objective: Our objective was to examine if markers of adipose tissue dysfunction, such as hypertrophy and macrophage accumulation, are relevant for the pathophysiology of breast cancer and its associated prognostic factors in a well-characterised cohort of women with breast cancer who did not receive treatment before surgery., Methods: A consecutive series of 164 women with breast cancer provided breast adipose tissue sample. Multivariate generalised linear models were used to test associations of anthropometric indices and prognostic factors with markers of adipose tissue dysfunction., Results: We found associations of breast adipocyte size and macrophage infiltration (number of CD68+ cells/100 adipocytes) with adiposity, particularly a strong association between breast adipocyte size and central obesity, independent of total adiposity, age and menopausal status (β adj  = 0.87; p = 0.0001). We also identified relationships of adipocyte hypertrophy and macrophage infiltration with prognostic factors, such as cancer stage and tumour grade (p < 0.05). RNA expression of pro-inflammatory cytokines (IL6, TNF) and leptin was also increased as a function of adipocyte size and CD86+/CD11c+ macrophage number/100 adipocytes (p < 0.05)., Conclusions: Our findings support the model of dysfunctional adipose tissue in obesity-associated breast cancer.

Adipose tissue is a complex endocrine organ, with a role in obesity and cancer. Adipose tissue is generally linked to excessive body fat, and it is well known that the female breast is rich in adipose tissue. Hence, one can wonder: what is the role of adipose tissue in the breast and why is it required? Adipose tissue as an organ consists of adipocytes, an extracellular matrix (ECM) and immune cells, with a significant role in the dynamics of breast changes throughout the life span of a female breast from puberty, pregnancy, lactation and involution. In this review, we will discuss the importance of breast adipose tissue in breast development and its involvement in breast changes happening during pregnancy, lactation and involution. We will focus on understanding the biology of breast adipose tissue, with an overview on its involvement in the various steps of breast cancer development and progression. The interaction between the breast adipose tissue surrounding cancer cells and vice-versa modifies the tumor microenvironment in favor of cancer. Understanding this mutual interaction and the role of breast adipose tissue in the tumor microenvironment could potentially raise the possibility of overcoming breast adipose tissue mediated resistance to therapies and finding novel candidates to target breast cancer.

Physical activity is associated with decreased breast cancer risk. The underlying biological mechanisms could include the reduction of the local inflammation in the breast tissue. We conducted a cross-sectional study to assess the association between the physical activity and the protein expression levels of eleven mediators of inflammation in normal breast tissue of 164 women having breast cancer. Information on total physical activity (household, occupational and recreational) performed during a one-year period was collected using a questionnaire. Normal breast tissue was obtained from mastectomy blocks distant from the tumor. The expression of the mediators of inflammation in normal breast tissue was visually evaluated by immunohistochemistry. Multivariate linear regression analyses were used to assess the prevalence ratios (PR) and 95% confidence intervals (CI) for higher protein expression levels of the mediators of inflammation in normal breast tissue across quartiles of physical activity. Higher total physical activity was associated with lower expression levels of the pro-inflammatory mediator TNF-α in normal breast epithelial tissue among all (PR=0.64, 95% CI=0.44-0.93 for the fourth quartile; P trend =0.013), premenopausal (PR=0.61, 95% CI=0.41-0.91 for the fourth quartile; P trend =0.014) and postmenopausal women (PR=0.45, 95% CI=0.21-0.96 for the fourth quartile; P trend =0.022). Conversely, higher total physical activity was associated with higher expression levels of the anti-inflammatory mediator IL-10 in normal breast epithelial tissue among all (PR=1.66, 95% CI=0.97-2.85 for the fourth quartile; P trend =0.071) and postmenopausal women (PR=4.69, 95% CI=1.26-17.43 for the fourth quartile; P trend =0.010). Our findings suggest a beneficial effect of physical activity on the local inflammatory profile in the breast tissue., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Chronic inflammation may be a causative factor in breast cancer. One possible underlying mechanism is the generation of oxidative stress, which may favor tumorigenic processes. Antioxidant consumption may, therefore, help reduce tissue inflammation levels. However, few studies have explored this relation in breast tissue. We aimed to evaluate correlations between antioxidant (vitamin A/retinol, vitamin C, vitamin E, β-carotene, α-carotene, lycopene, lutein/zeaxanthin, β-cryptoxanthin, selenium, and zinc) intakes and protein expression levels of interleukin (IL)-6, tumor necrosis factor-α, C-reactive protein, cyclooxygenase-2, leptin, serum amyloid A1, signal transducer and activator of transcription 3, IL-8, IL-10, lactoferrin, and transforming growth factor-β measured in the normal breast tissue of 160 women diagnosed with breast cancer. Antioxidant intakes were collected using a self-administered food frequency questionnaire. Inflammation marker expression was assessed by immunohistochemistry. Correlations between antioxidant intakes and inflammatory marker expression were evaluated using Spearman's partial correlation coefficients ( r) for all women and for premenopausal and postmenopausal women separately. After Bonferroni correction, negative correlations were observed between dietary β-tocopherol and IL-10 expression in all women combined ( r = -0.26, P = .003) and among postmenopausal women ( r = -0.39, P = .003). For all women, a negative correlation was found between total zinc intakes and IL-10 ( r = -0.26, P = .002). Among postmenopausal women, dietary selenium intake was negatively correlated with the expression of lactoferrin ( r = -0.39, P = .003). No associations were observed in premenopausal women. Our findings suggest that consumption of specific antioxidants, including β-tocopherol, zinc, and selenium, may act on the breast tissue through mechanisms affecting the expression of some inflammation markers, particularly among postmenopausal women.

Objective: Inflammatory markers may be associated with breast cancer risk. We assessed the association between expression levels of proinflammatory (interleukin 6, tumor necrosis factor-α, C-reactive protein, cyclooxygenase 2, leptin, serum amyloid A1, interleukin 8, and signal transducer and activator of transcription 3) and anti-inflammatory markers (transforming growth factor-β, interleukin 10, and lactoferrin) in normal breast tissue with mammographic density, a strong breast cancer risk indicator, among 163 breast cancer patients., Methods: The expression of inflammatory markers was visually evaluated on immunohistochemistry stained slides. The percent mammographic density (PMD) was estimated by a computer-assisted method in the contralateral cancer-free breast. We used generalized linear models to estimate means of PMD by median expression levels of the inflammatory markers while adjusting for age and waist circumference., Results: Higher expression levels (above median) of the proinflammatory marker interleukin 6 were associated with higher PMD among all women (24.1% vs 18.5%, P = 0.007). Similarly, higher expression levels (above median) of the proinflammatory markers (interleukin 6, tumor necrosis factor-α, C-reactive protein, and interleukin 8) were associated with higher PMD among premenopausal women (absolute difference in the PMD of 8.8% [P = 0.006], 7.7% [P = 0.022], 6.7% [P = 0.037], and 16.5% [P = 0.032], respectively). Higher expression levels (above median) of the anti-inflammatory marker transforming growth factor-β were associated with lower PMD among all (18.8% vs 24.3%, P = 0.005) and postmenopausal women (14.5% vs 20.7%, P = 0.013)., Conclusions: Our results provide support for the hypothesized role of inflammatory markers in breast carcinogenesis through their effects on mammographic density. Inflammatory markers could be targeted in future breast cancer prevention interventions.

Amplification of the human epidermal growth factor receptor 2 (HER2) gene is associated with worse prognosis and decreased overall survival in breast cancer patients. The HER2 gene contains several polymorphisms; two of the best-characterized HER2 polymorphisms are Ile655Val and Ala1170Pro. The aim of this study was to evaluate the association between these two HER2 polymorphisms in normal breast and breast cancer tissues and known breast cancer prognostic factors in a retrospective cohort study of 73 women with non-metastatic HER2-positive breast cancer. HER2 polymorphisms were assessed in breast cancer tissue and normal breast tissue using TaqMan assay. Ala1170Pro polymorphism in normal breast tissue was associated with age at diagnosis (p = 0.007), tumor size (p = 0.004) and lymphovascular invasion (p = 0.06). Similar significant associations in cancer tissues were observed. No association between the Ile655Val polymorphism and prognostic factors were observed. However, we found significant differences in the distribution of Ile655Val (p = 0.03) and Ala1170Pro (p = 0.01) genotypes between normal breast and breast tumor tissues. This study demonstrates that only the Ala1170Pro polymorphism is associated with prognostic factors in HER2-positive breast cancer patients. Moreover, our results suggest that both HER2 polymorphisms could play a significant role in carcinogenesis in non-metastatic HER2-positive breast cancer women., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the association between anthropometric factors, weight gain during adulthood, and mammographic features among 1,435 women recruited at screening mammography., Methods: Spearman's partial coefficients were used to evaluate the correlation of anthropometric factors with mammographic features (percent density, absolute dense area, and non-dense area). Multivariate generalized linear models were used to evaluate the associations between weight change categories and mammographic features., Results: Body mass index was inversely correlated with percent density (r = -0.49, p < 0.0001) or absolute dense area (r = -0.21, p < 0.0001) and positively correlated with absolute non-dense area (r = 0.69, p < 0.0001). However, body mass index was positively correlated with absolute dense area when adjusting for absolute non-dense area (r = 0.16, p < 0.0001). Similar results were observed for weight, waist circumference, and waist-to-hip ratio with mammographic features. Within increasing categories of weight change, percent density (p trend < 0.0001) and absolute dense area (p trend = 0.025) increased, while absolute non-dense area decreased (p trend < 0.0001). After stratification by the median of non-dense area, the positive association between weight gain and absolute dense area remained only among women with higher non-dense area., Conclusions: Adiposity seems positively associated with both dense and non-dense areas following adjustment for each other. Our findings suggest a higher breast dense area among women who gained weight and that a minimum of breast fat may be needed to promote the proliferation of this fibroglandular tissue.

Previous studies have shown that 4-54% of breast lesions reported on core biopsies as atypical ductal hyperplasia (ADH) are upgraded on further excision to ductal carcinoma in situ (DCIS) or invasive carcinoma. We evaluated the rate of upgrading ADH to carcinoma at surgery for ADH diagnosed by percutaneous biopsy, and examined characteristics associated with malignancy. We identified 13,488 consecutive biopsies conducted at one center over a nine-year period. A total of 422 biopsies with ADH in 415 patients were included. DCIS or invasive carcinoma was found in 132 cases (31.3% upgrading). Multivariate model revealed that ipsilateral breast symptoms, mammographic lesion other than microcalcifications alone, 14G core needle biopsy, papilloma co-diagnosis, severe ADH and pathologists with lower volume of ADH diagnosis were factors statistically associated with malignancy. However, no subgroups were identified for safe clinical-only follow-up. Surgery is recommended in all cases of ADH diagnosed by percutaneous breast biopsy., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: The effect of multivitamin-multimineral supplements on the occurrence of chronic diseases, such as breast cancer, is unclear. Breast density is increasingly used as a biomarker of breast cancer risk., Objective: The present study evaluated the association of multivitamin-multimineral supplement use with breast density., Design: Premenopausal (n = 777) and postmenopausal (n = 783) women were recruited at the time of screening mammography. Anthropometric measurements were taken at recruitment. Demographic characteristics, behavioral factors, and health conditions were documented by telephone interview. Diet and multivitamin-multimineral and individual vitamin and mineral supplement use were assessed with a self-administered food-frequency questionnaire. Breast density from screening mammograms was measured using a computer-assisted method. Crude and adjusted means in breast density were evaluated according to multivitamin-multimineral supplement use using generalized linear models., Results: Current multivitamin-multimineral supplement use was reported by 21.7% of women (20.7% and 22.6% of premenopausal and postmenopausal women, respectively). Premenopausal women who were currently using multivitamin-multimineral supplements had higher adjusted mean breast density (45.5%) than past (42.9%) or never (40.2%) users (P for heterogeneity = 0.03, P for trend = 0.009). Of the current users, breast density was not related to duration of multivitamin-multimineral supplement use. In postmenopausal women, multivitamin-multimineral supplement use was not associated with breast density (P for heterogeneity = 0.53, P for trend = 0.40)., Conclusion: Regular use of multivitamin-multimineral supplements may be associated with higher mean breast density among premenopausal women. The relations of multivitamin-multimineral supplement use to breast density and breast cancer risk need to be clarified.

The insulin-like growth factor (IGF) pathway is believed to play a role in carcinogenesis of the mammary gland. Single nucleotide polymorphisms (SNPs) of IGF-I, IGF-binding protein-3 (IGFBP-3), IGF receptor 1, insulin receptor substrate 1, and phosphoinositide-3-kinase, catalytic, beta polypeptide genes, which are members of the IGF pathway, have been associated with risk of common cancers, breast density, and/or IGF levels but results remain inconclusive. Thus, we evaluated the association of 11 targeted IGF pathway SNPs with circulating IGF levels and mammographic breast density. Among 741 white premenopausal women, blood samples were collected at time of screening mammography, and plasma IGF-I and IGFBP-3 levels were measured by ELISA. Percent and absolute breast density were estimated using a computer-assisted method. Multivariate linear models were used to examine the associations. Women carrying increasing number of copies of the rare allele of IGF-I rs1520220 and rs6220 SNPs had increased percent breast density (P(trend) = 0.04 and 0.06, respectively). Carriers of increasing number of copies of the rare allele of phosphoinositide-3-kinase, catalytic, beta polypeptide rs361072 SNP had decreased percent (P(trend) = 0.04) and absolute (P(trend) = 0.02) breast density. An association of insulin receptor substrate 1 rs1801278 SNP with absolute density (P(trend) = 0.03) was also observed. All four IGFBP-3 SNPs (including rs2854744) were associated with IGF-I and IGFBP-3 levels. This study shows that several components of the IGF pathway are associated with breast density or IGF levels. Our findings provide additional support for the idea that several components of the IGF pathway may affect breast cancer risk and that this effect on breast cancer development may be mediated, at least in part, through its influence on the morphogenesis of breast tissue.

Background: Dietary vitamin D has been associated with lower mammographic breast density, a strong biomarker for breast cancer risk. Blood 25-hydroxyvitamin D [25(OH)D] is an integrated measure of vitamin D status (from food, supplements, and sun exposure) and varies with season. Our objective was to assess seasonal variations of breast density and compare such variations, if any, with that of 25(OH)D., Methods: This cross-sectional study includes 741 premenopausal women recruited at screening mammography. Plasma 25(OH)D at recruitment was measured by RIA. Breast density was evaluated using a computer-assisted method. Seasonal variations were modeled using multivariate linear regression and semi-parametric cubic smoothing splines., Results: Season was strongly associated with 25(OH)D (P < 0.0001). The highest smoothed mean 25(OH)D levels were seen at the end of July (81.5 nmol/L) and the lowest in mid-April (52.4 nmol/L). Breast density showed modest seasonal variations (P = 0.028). The lowest smoothed mean breast density was observed in early December (38.5%) and the highest at the beginning of April (44.3%). When a 4-month lag time was presumed, seasonal variations of breast density appeared to be a mirror image of those of 25(OH)D, and the correlation of daily smoothed estimates of mean breast density and 25(OH)D was negative and strong (r = -0.90)., Conclusion: In premenopausal women, changes in blood vitamin D seem to be inversely related to changes in breast density with a lag time of about 4 months. This finding encourages further investigation of the possibility that vitamin D could reduce breast density and breast cancer risk.

Diets with higher vitamin D and calcium contents were found associated with lower mammographic breast density and breast cancer risk in premenopausal women. Because laboratory studies suggest that the actions of vitamin D, calcium, insulin-like growth factor (IGF)-I, and IGF-binding protein-3 (IGFBP-3) on human breast cancer cells are interrelated, we examined whether IGF-I and IGFBP-3 levels could affect the strength of the association of vitamin D and calcium intakes with breast density. Among 771 premenopausal women, breast density was measured by a computer-assisted method, vitamin D and calcium intakes by a food frequency questionnaire, and levels of plasma IGF-I and IGFBP-3 by ELISA methods. Multivariate linear regression models were used to examine the associations and the interactions. The negative associations of vitamin D or calcium intakes with breast density were stronger among women with IGF-I levels above the median (beta = -2.8, P = 0.002 and beta = -2.5, P = 0.002, respectively) compared with those with IGF-I levels below or equal to the median (beta = -0.8, P = 0.38 and beta = -1.1, P = 0.21; P(interaction) = 0.09 and 0.16, respectively). Similar results were observed within levels of IGFBP-3 (P(interaction) = 0.06 and 0.03, respectively). This is the first study to report that the negative relation of vitamin D and calcium intakes with breast density may be seen primarily among women with high IGF-I or high IGFBP-3 levels. Our findings suggest that the IGF axis should be taken into account when the effects of vitamin D and calcium on breast density (and perhaps breast cancer risk) are examined at least among premenopausal women.

Members of the insulin-like growth factor family have been associated with breast cancer risk and mammographic breast density, one of the strongest known breast cancer risk indicators. The aim of this cross-sectional study was to examine the association of levels of C-peptide (a marker of insulin secretion) with mammographic breast density among 1,499 healthy women recruited during screening mammography examinations. At time of mammography, blood samples and time since last meal were collected. Plasma C-peptide levels were measured by ELISA method, and mammographic breast density by a computer-assisted method. Spearman's partial correlation coefficients, adjusting for age and time since last meal (when necessary), were used to evaluate the associations. High body mass index and waist-to-hip ratio measurements were independently correlated with high levels of C-peptide (r(s) = 0.173 and r(s) = 0.252, respectively; P < 0.0001) or low breast density (r(s) = -0.389 and r(s) = -0.142, respectively; P < 0.0001). High levels of C-peptide were correlated with low breast density (r(s) = -0.210, P < 0.0001). However, the strength of the negative correlation was substantially reduced and was no longer significant after further adjustment for body mass index and waist-to-hip ratio (r(s) = -0.022, P = 0.41). These results suggest that C-peptide levels are not associated with breast density after complete adjustment for adiposity. Thus, the insulin/C-peptide-breast density relation does not seem to mirror the insulin/C-peptide-breast cancer association.

Background: A better understanding of factors that affect breast density, one of the strongest breast cancer risk indicators, may provide important clues about breast cancer etiology and prevention. This study evaluates the association of vitamin D and calcium, from food and/or supplements, to breast density in premenopausal and postmenopausal women separately., Methods: A total of 777 premenopausal and 783 post-menopausal women recruited at two radiology clinics in Quebec City, Canada, in 2001 to 2002, completed a food frequency questionnaire to assess vitamin D and calcium. Breast density from screening mammograms was assessed using a computer-assisted method. Associations between vitamin D or calcium and breast density were evaluated using linear regression models. Adjusted means in breast density were assessed according to the combined daily intakes of the two nutrients using generalized linear models., Results: In premenopausal women, total intakes of vitamin D and calcium were inversely related to breast density (beta = -1.4; P = 0.004 for vitamin D; beta = -0.8; P = 0.0004 for calcium). In multivariate linear regression, simultaneous increments in daily total intakes of 400 IU vitamin D and 1,000 mg calcium were associated with an 8.5% (95% confidence interval, 1.8-15.1) lower mean breast density. The negative association between dietary vitamin D intake and breast density tended to be stronger at higher levels of calcium intake and vice versa. Among postmenopausal women, intakes of vitamin D and calcium were not associated with breast density., Conclusion: These findings show that higher intakes of vitamin D and calcium from food and supplements are related to lower levels of breast density among premenopausal women. They suggest that increasing intakes of vitamin D and calcium may represent a safe and inexpensive strategy for breast cancer prevention.

Some studies have suggested that insulin-like growth factor (IGF) pathway is related to premenopausal breast density, one of the strongest known breast cancer risk factors. This study was designed specifically to test the hypothesis that higher levels of IGF-I and lower levels of IGF-binding protein (IGFBP)-3 are associated with high mammographic breast density among premenopausal but not among postmenopausal women. A total of 783 premenopausal and 791 postmenopausal healthy women were recruited during screening mammography examinations. Blood samples were collected at the time of mammography, and plasma IGF-I and IGFBP-3 levels were measured by ELISA. Mammographic breast density was estimated using a computer-assisted method. Spearman's partial correlation coefficients (r(s)) were used to evaluate the associations. Adjusted mean breast density was assessed by joint levels of IGF-I and IGFBP-3 using generalized linear models. Among premenopausal women, high levels of IGF-I and low levels of IGFBP-3 were independently correlated with high breast density (r(s) = 0.083; P = 0.021 and r(s) = -0.124; P = 0.0005, respectively). Correlation of IGF-I with breast density was stronger among women in the lowest tertile of IGFBP-3 than among those in the highest tertile of IGFBP-3 (r(s) = 0.138; P = 0.027 and r(s) = -0.039; P = 0.530, respectively). In contrast, the correlation of IGFBP-3 with breast density was stronger among women in the highest tertile of IGF-I than among those in the lowest tertile of IGF-I (r(s) = -0.150; P = 0.016 and r(s) = -0.008; P = 0.904, respectively). Women in the combined top tertile of IGF-I and bottom tertile of IGFBP-3 had higher mean breast density than those in the combined bottom tertile of IGF-I and top tertile of IGFBP-3 (53.8% versus 40.9%; P = 0.014). No significant association was observed among postmenopausal women. Our findings confirm that IGF-I and IGFBP-3 are associated with breast density among premenopausal women. They provide additional support for the idea that, among premenopausal women, these growth factors may affect breast cancer risk, at least in part, through their influence on breast tissue morphology as reflected on mammogram.