Local Biomarkers Involved in the Interplay between Obesity and Breast Cancer

Obesity is associated with an increased risk of breast cancer, which is the most common cancer in women worldwide (excluding non-melanoma skin cancer). Furthermore, breast cancer patients with obesity have an impaired prognosis. Adipose tissue is abundant in the breast. Therefore, breast cancer develops in an adipose-rich environment. During obesity, changes in the local environment in the breast occur which are associated with breast cancer. A shift towards a pro-inflammatory state is seen, resulting in altered levels of cytokines and immune cells. Levels of adipokines, such as leptin, adiponectin, and resistin, are changed. Aromatase activity rises, resulting in higher levels of potent estrogen in the breast. Lastly, remodeling of the extracellular matrix takes place. In this review, we address the current knowledge on the changes in the breast adipose tissue in obesity associated with breast cancer initiation and progression. We aim to identify obesity-associated biomarkers in the breast involved in the interplay between obesity and breast cancer. Hereby, we can improve identification of women with obesity with an increased risk of breast cancer and an impaired prognosis. Studies investigating mammary adipocytes and breast adipose tissue in women with obesity versus women without obesity are, however, sparse and further research is needed.

Bisphenol-A in biological samples of breast cancer mastectomy and mammoplasty patients and correlation with levels measured in urine and tissue

Endocrine disrupting chemicals (EDCs) are organic compounds that have estrogenic activity and can interfere with the endocrine system. Bisphenol-A (BPA) is one of these compounds which possess a potential risk for breast cancer. The aim of this research was to evaluate BPA concentration in both the urine and breast adipose tissue samples of breast cancer mastectomy and mammoplasty patients and study correlations of BPA levels in breast adipose tissue with urine samples in the both groups. Urine and breast adipose tissue samples from 41 breast cancer mastectomy and 11 mammoplasty patients were taken. BPA concentrations were detected using an ELISA assay. Urinary BPA concentrations were significantly higher in cancerous patients (2.12 ± 1.48 ng/ml; P < 0.01) compared to non-cancerous (0.91 ± 0.42 ng/ml). Likewise, tissue BPA concentrations in cancerous patients (4.20 ± 2.40 ng/g tissue; P < 0.01) were significantly higher than non- cancerous (1.80 ± 1.05 ng/g tissue). Urinary BPA concentrations were positively correlated with breast adipose tissue BPA in the case group (P < 0.001, R = 0.896). We showed that BPA was present in urine and breast adipose tissue samples of the studied populations. With regard to higher BPA mean concentration in cancerous patients than non-cancerous individuals in this study, BPA might increase the risk of breast cancer incidence.

Associations of Biomarkers of Inflammation and Breast Cancer in the Breast Adipose Tissue of Women with Combined Measures of Adiposity

Background. Mechanisms underlying the obesity-breast cancer link involve inflammation but need to be elucidated. Determining obesity by combining body mass index (BMI) with the waist circumference (WC) may clarify the role of inflammatory and hormonally related markers in breast cancer. We examined the effect of combining adiposity indices (BMI/WC) with the gene expression of several biomarkers involved in breast cancer. Methods. Expression of cytochrome P450 family 19 subfamily A member 1 (CYP19A1), estrogen receptor-alpha (ER-α), allograft inflammatory factor 1 (AIF1), cyclooxygenase-2 (COX2), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and leptin (LEP) in 141 adipose breast tissues was quantified using qPCR method. BMI and WC were measured by a trained nurse and categorized using the median split, BMILOWCLO, BMILOWCHI, BMIHIWCLO, and BMIHIWCHI. Results. Gene expression of IL-6 (3-fold), TNF-α (2-fold), and LEP (2-fold) was higher in the breast adipose tissue of women with high WC regardless of BMI, that is, BMILOWCHI and BMIHIWCHI women (all P < 0.01). Compared to BMILOWCLO women, gene expression of CYP19A1, COX2, and AIF1 was increased by two-fold in breast adipose tissue of BMIHIWCHI women ( P < 0.10). ER-α was not different across adiposity categories. Conclusions. The expression of some biomarkers, particularly those related to inflammation, is elevated in breast adipose tissue of women with a high WC independent of BMI. Obesity monitoring should also include women with normal or low BMI, but with central adiposity.

Breast adipose regulation of premenopausal breast epithelial phenotype involves interleukin 10

Epidemiological studies inversely associate body mass index (BMI) with breast cancer risk in premenopausal women, but the pathophysiological linkage remains ill-defined. Despite the documented relevance of the ‘local’ environment to breast cancer progression and the well-accepted differences in transcriptome and metabolic properties of anatomically distinct fat depots, specific breast adipose contributions to the proliferative potential of non-diseased breast glandular compartment are not fully understood. To address early breast cancer causation in the context of obesity status, we compared the cellular and molecular phenotypes of breast adipose and matched breast glandular tissue from premenopausal non-obese (mean BMI=27 kg/m2) and obese (mean BMI=44 kg/m2) women. Breast adipose from obese women showed higher expression levels of adipogenic, pro-inflammatory and estrogen synthetic genes, than from non-obese women. Obese breast glandular tissue displayed lower proliferation and inflammatory status and higher expression of anti-proliferative/pro-senescence biomarkers TP53 and p21, than from non-obese women. Transcript levels for T-cell receptor and co-receptors CD3 and CD4 were higher in breast adipose of obese cohorts, coincident with elevated adipose Interleukin 10 (IL10) and FOXP3 gene expression. In human breast epithelial cell lines MCF10A and HMEC, recombinant human IL10 reduced cell viability and CCND1 transcript levels, increased those of TP53 and p21, and promoted (MCF10A) apoptosis. Our findings suggest that breast adipose-associated IL10 may mediate paracrine interactions between non-diseased breast adipose and breast glandular compartments and highlight how breast adipose may program the local inflammatory milieu, partly by recruiting FOXP3+ T regulatory cells, to influence premenopausal breast cancer risk.

Breast adipose tissue macrophages (BATMs) have a stronger correlation with breast cancer survival than breast tumor stroma macrophages (BTSMs)

Background An abundance of tumor-associated macrophages has been shown to be an independent prognostic factor for a poor prognosis of human breast cancer (BC). Adipose tissue accounts for the largest proportion of the breast and has also been identified as an independent indicator of poor survival in BC. This study aims to elucidate if the influence of adipose tissue in BC might be mediated by macrophages. The roles of macrophages in the breast tumor-stroma (breast tumor stroma macrophages, BTSM) and macrophages in the surrounding adipose tissue (breast adipose tissue macrophages, BATM) were explored separately. Methods Two hundred ninety-eight BC tissue samples were analyzed immunohistochemically. The number of macrophages was detected by CD68+ staining. The quantity of BATMs and BTSMs was correlated to clinical and pathological parameters as well as to disease-free survival (DFS) and overall survival (OS). Results The amounts of BATMs and BTSMs strongly correlated with each other (r = 0.5, p = 2.98E−15). The quantity of BTSMs, but not of BATMs, was significantly associated with the BC molecular subtype (p = 0.000011), and all triple-negative BC tumors contained high amounts of BTSMs. BATMs were negatively associated with DFS (p = 0.0332). Both BATMs (p = 0.000401) and BTSMs (p = 0.021) were negatively associated with OS in the Kaplan-Meier analysis, but only BATMs remained an independent factor in the multivariate Cox-regression analysis (HR = 4.464, p = 0.004). Combining prostaglandin E2 receptor 3 (EP3)-expression and the quantity of BATMs, a subgroup with an extremely poor prognosis could be identified (median OS 2.31 years in the “high BATMs/low EP3” subgroup compared to 11.42 years in the most favorable “low BATMs/high EP3” subgroup, p = 0.000002). Conclusion Our findings suggest that BTSMs and BATMs seem to be involved differently in BC. Breast adipose tissue might contribute to the aggressiveness of BC via BATMs, which were independently associated with BC survival. BATMs’ role and occurrence might be functionally dependent on EP3, as a combination of both factors was strongly associated with survival. Targeting BATMs—eventually in combination with targeting the EP3-pathway—might be promising for future therapies.

Obese Adipose Tissue as a Driver of Breast Cancer Growth and Development: Update and Emerging Evidence

Obesity is an established risk factor for breast cancer growth and progression. A number of advances have been made in recent years revealing new insights into this link. Early events in breast cancer development involve the neoplastic transformation of breast epithelial cells to cancer cells. In obesity, breast adipose tissue undergoes significant hormonal and inflammatory changes that create a mitogenic microenvironment. Many factors that are produced in obesity have also been shown to promote tumorigenesis. Given that breast epithelial cells are surrounded by adipose tissue, the crosstalk between the adipose compartment and breast epithelial cells is hypothesized to be a significant player in the initiation and progression of breast cancer in individuals with excess adiposity. The present review examines this crosstalk with a focus on obese breast adipose-derived estrogen, inflammatory mediators and adipokines, and how they are mechanistically linked to breast cancer risk and growth through stimulation of oxidative stress, DNA damage, and pro-oncogenic transcriptional programs. Pharmacological and lifestyle strategies targeting these factors and their downstream effects are evaluated for feasibility and efficacy in decreasing the risk of obesity-induced breast epithelial cell transformation and consequently, breast cancer development.

Breast adipocyte size associates with ipsilateral invasive breast cancer risk after ductal carcinoma in situ

Although ductal carcinoma in situ (DCIS) is a non-obligate precursor to ipsilateral invasive breast cancer (iIBC), most DCIS lesions remain indolent. Hence, overdiagnosis and overtreatment of DCIS is a major concern. There is an urgent need for prognostic markers that can distinguish harmless from potentially hazardous DCIS. We hypothesised that features of the breast adipose tissue may be associated with risk of subsequent iIBC. We performed a case–control study nested in a population-based DCIS cohort, consisting of 2658 women diagnosed with primary DCIS between 1989 and 2005, uniformly treated with breast conserving surgery (BCS) alone. We assessed breast adipose features with digital pathology (HALO®, Indica Labs) and related these to iIBC risk in 108 women that developed subsequent iIBC (cases) and 168 women who did not (controls) by conditional logistic regression, accounting for clinicopathological and immunohistochemistry variables. Large breast adipocyte size was significantly associated with iIBC risk (odds ratio (OR) 2.75, 95% confidence interval (95% CI) = 1.25–6.05). High cyclooxygenase (COX)-2 protein expression in the DCIS cells was also associated with subsequent iIBC (OR 3.70 (95% CI = 1.59–8.64). DCIS with both high COX-2 expression and large breast adipocytes was associated with a 12-fold higher risk (OR 12.0, 95% CI = 3.10–46.3, P < 0.001) for subsequent iIBC compared with women with smaller adipocyte size and low COX-2 expression. Large breast adipocytes combined with high COX-2 expression in DCIS is associated with a high risk of subsequent iIBC. Besides COX-2, adipocyte size has the potential to improve clinical management in patients diagnosed with primary DCIS.

Low Levels of Omega-3 Long-Chain Polyunsaturated Fatty Acids Are Associated with Bone Metastasis Formation in Premenopausal Women with Breast Cancer: A Retrospective Study

In the present study, we investigated various biochemical, clinical, and histological factors associated with bone metastases in a large cohort of pre- and postmenopausal women with breast cancer. Two hundred and sixty-one consecutive women with breast cancer were included in this study. Breast adipose tissue specimens were collected during surgery. After having established the fatty acid profile of breast adipose tissue by gas chromatography, we determined whether there were differences associated with the occurrence of bone metastases in these patients. Regarding the clinical and histological criteria, a majority of the patients with bone metastases (around 70%) had tumors with a luminal phenotype and 59% of them showed axillary lymph node involvement. Moreover, we found a negative association between the levels of n-3 long-chain polyunsaturated fatty acids (LC-PUFA) in breast adipose tissue and the development of bone metastases in premenopausal women. No significant association was observed in postmenopausal women. In addition to a luminal phenotype and axillary lymph node involvement, low levels of n-3 LC-PUFA in breast adipose tissue may constitute a risk factor that contributes to breast cancer bone metastases formation in premenopausal women.