Molecular Links between Central Obesity and Breast Cancer

Abstract

Worldwide, breast cancer (BC) is the most common malignancy in women, in regard to incidence and mortality. In recent years, the negative role of obesity during BC development and progression has been made abundantly clear in several studies. However, the distribution of body fat may be more important to analyze than the overall body weight. In our review of literature, we reported some key findings regarding the role of obesity in BC development, but focused more on central adiposity. Firstly, the adipose microenvironment in obese people bears many similarities with the tumor microenvironment, in respect to associated cellular composition, chronic low-grade inflammation, and high ratio of reactive oxygen species to antioxidants. Secondly, the adipose tissue functions as an endocrine organ, which in obese people produces a high level of tumor-promoting hormones, such as leptin and estrogen, and a low level of the tumor suppressor hormone, adiponectin. As follows, in BC this leads to the activation of oncogenic signaling pathways: NFκB, JAK, STAT3, AKT. Moreover, overall obesity, but especially central obesity, promotes a systemic and local low grade chronic inflammation that further stimulates the increase of tumor-promoting oxidative stress. Lastly, there is a constant exchange of information between BC cells and adipocytes, mediated especially by extracellular vesicles, and which changes the transcription profile of both cell types to an oncogenic one with the help of regulatory non-coding RNAs.

MTHFR, XRCC1 and OGG1 genetic polymorphisms in breast cancer: a case-control study in a population from North Sardinia

“…Several strong epidemiological and clinical studies support the correlation between mammary tumorigenesis, tumour progression and obesity. The main mechanisms underlying this link are capacity of conversion of androgenic precursors to estrogen through peripheral aromatization in adipose tissue, the alteration of physiological levels of insulin, insulin-like growth factor (IGF), adipokines, changes in the adipose tissue microenvironment and chronic lowgrade inflammation [33][34][35][36][37][38]. Juarez-Cruz JC et al [39] have recently shown that the leptin, a hormone secreted by adipocytes, through the FAK and Src kinases activation, contributes to BC progression.…”

Immunohistochemical analysis of adipokine and adipokine receptor expression in the breast tumor microenvironment: associations of lower leptin receptor expression with estrogen receptor-negative status and triple-negative subtype

“…These findings suggest that lower expression of LEPR (rather than higher expression as hypothesized) is an important indicator of more aggressive breast cancer, independent of race, BMI, and menopausal status, and might serve as an important biomarker associated with disparate outcomes, particularly among Black women. This seemingly counterintuitive observation is partially supported by data suggesting complex associations of obesity/adiposity, LEP/LEPR's activation of various signaling pathways, and breast cancer progression, which is further complicated by ER expression [46,47]. We hypothesize that central adiposity (rather than general obesity, as measured by BMI) is the etiologic mechanism linking LEPR expression in the breast tumor microenvironment with aggressive tumor clinicopathology and ultimately poorer prognosis.…”

Serum Iron Status and the Risk of Breast Cancer in Europeans: A 2-Sample Mendelian Randomisation Study

“…Breast cancer is a heterogeneous disease with histopathology and molecular subtypes determining different clinical prognosis and risk factors [32]. Previous studies suggested that obesity may increase the risk of breast cancer [33]. Furthermore, BMI has been related to iron concentrations and breast cancer risk [34,35].…”