The Effects of Adipocytes on the Regulation of Breast Cancer in the Tumor Microenvironment: An Update

Abstract

Obesity is a global pandemic and it is well evident that obesity is associated with the development of many disorders including many cancer types. Breast cancer is one of that associated with a high mortality rate. Adipocytes, a major cellular component in adipose tissue, are dysfunctional during obesity and also known to promote breast cancer development both in vitro and in vivo. Dysfunctional adipocytes can release metabolic substrates, adipokines, and cytokines, which promote proliferation, progression, invasion, and migration of breast cancer cells. The secretion of adipocytes can alter gene expression profile, induce inflammation and hypoxia, as well as inhibit apoptosis. It is known that excessive free fatty acids, cholesterol, triglycerides, hormones, leptin, interleukins, and chemokines upregulate breast cancer development. Interestingly, adiponectin is the only adipokine that has anti-tumor properties. Moreover, adipocytes are also related to chemotherapeutic resistance, resulting in the poorer outcome of treatment and advanced stages in breast cancer. Evaluation of the adipocyte secretion levels in the circulation can be useful for prognosis and evaluation of the effectiveness of cancer therapy in the patients. Therefore, understanding about functions of adipocytes as well as obesity in breast cancer may reveal novel targets that support the development of new anti-tumor therapy. In this systemic review, we summarize and update the effects of secreted factors by adipocytes on the regulation of breast cancer in the tumor microenvironment.

Interfering Role of ERα on Adiponectin Action in Breast Cancer

“…Hypertrophic and hyperplastic adipocytes through their metabolic substrates, such as both saturated and unsaturated fatty acids (FAs) and matrix metalloproteinase (MMPs), regulate breast cancer biology. FAs are stored as lipid droplet in the adipose tissue and their release, induced by highfat diet and obese status, may contribute to angiogenesis and inflammation, key steps of tumor development and progression (47). Mostly, FAs can activate toll-like receptor 4 and NF-kB/TNF-α signaling.…”

“…Moreover, adipocytes produce molecules, defined as "released hormones, " including estrogens and adipokines. In post-menopausal obese patients, the elevated level of estrogens, produced by aromatase highly expressed in adipocytes, activates ERα, promoting breast cancer cell growth and progression (47). Furthermore, changes in adipokines profile, due to the altered fat distribution and function, is one of the main features in obese state.…”

Pathological Crosstalk between Metastatic Breast Cancer Cells and the Bone Microenvironment

“…This is achieved by the activation of different pathways including mTOR and NF-K B signaling in the breast cancer cells. Unfortunately, this antitumor effect is diminished in obesity due to reduced expression of adiponectin receptors leading to therapy resistance [75]. Controversially, other studies have shown that adiponectin can stimulate breast cancer migration and growth [76,77].…”

“…Controversially, other studies have shown that adiponectin can stimulate breast cancer migration and growth [76,77]. In contrast, leptin has a protumor effect and is associated with increased metastasis [75,78]. For example, adipocyte-derived leptin and IL-1β increase breast cancer cell colonization and migration to the adipose tissue adipocytes of the skeleton [79].…”

“…Overexpression stimulates metastasis via AKT signaling [106] Adipocytes Lipids Lipids act as energy source for cancer cells, affect their metabolism and increase their invasiveness [67,[72][73][74] Adipokines Adiponectin has anti-tumoral effects via mTOR and NF-K B signaling [75] Leptin promotes metastasis via regulation of VEGF [80] Author Contributions: J.Z., M.-T.H., and H.T. reviewed literature and wrote the manuscript; D.J.S.…”