Advances in the Prevention and Treatment of Obesity-Driven Effects in Breast Cancers

Abstract

Obesity and associated chronic inflammation were shown to facilitate breast cancer (BC) growth and metastasis. Leptin, adiponectin, estrogen, and several pro-inflammatory cytokines are involved in the development of obesity-driven BC through the activation of multiple oncogenic and pro-inflammatory pathways. The aim of this study was to assess the reported mechanisms of obesity-induced breast carcinogenesis and effectiveness of conventional and complementary BC therapies. We screened published original articles, reviews, and meta-analyses that addressed the involvement of obesity-related signaling mechanisms in BC development, BC treatment/prevention approaches, and posttreatment complications. PubMed, Medline, eMedicine, National Library of Medicine (NLM), and ReleMed databases were used to retrieve relevant studies using a set of keywords, including "obesity," "oncogenic signaling pathways," "inflammation," "surgery," "radiotherapy," "conventional therapies," and "diet." Multiple studies indicated that effective BC treatment requires the involvement of diet- and exercise-based approaches in obese postmenopausal women. Furthermore, active lifestyle and diet-related interventions improved the patients' overall quality of life and minimized adverse side effects after traditional BC treatment, including postsurgical lymphedema, post-chemo nausea, vomiting, and fatigue. Further investigation of beneficial effects of diet and physical activity may help improve obesity-linked cancer therapies.

Keywords: breast cancer; estrogen; inflammation; neoadjuvant therapy; obesity; oncogenic signaling; preventive measures.

Figure 1

The role of obesity in the stimulation of carcinogenesis (71). Chronic low level of inflammation was reported in obese individuals and associated with the inflammatory immune responses initiated by the death of adipocytes. During this process, M1 macrophages are accumulated and form a crown-like structure, which provokes cell cycle progression in adipose stromal cells of the breast via secretion of inflammatory mediators (TNF-α, IL-6, IL-11) and activation of NF-κB. tumor necrosis factor-alpha, TNF-a; interleukin 6, IL-6; interleukin 11, IL-11; nuclear factor kappa-light-chain-enhancer of activated B cells, NF-kB.

Figure 2

The activity of various oncogenic pathways triggers BC epithelial cell proliferation and tumor progression. Obesity-induced chronic inflammation can promote the NF-κB signaling. Fat cell-produced estrone can enhance the activation of NF-κB and promote BC progression. Leptin can modulate the PI3K/AKT signaling through IRS-1, enhance mTOR activity, trigger 4EBP1 and elF4E phosphorylation, and mediate the STAT3-promoted gene transcription required for cancer cell growth. Furthermore, the JAK-STAT and MAPK pathways are enhanced by the leptin-induced JAK2 signaling. MEK phosphorylation strongly promotes gene expression for efficient tumor progression. Aromatase activity promotes the androgen to estrogen conversion required for tumor progression. Other signaling effectors such as insulin, estradiol, adipokines, and high glucose can also enhance BC progression. Insulin can promote IRS and Tyr-P signaling and induce the activation of PI3K/AKT via stimulation of GLUT-4, which consequently enhances the glucose uptake into BC cells. Several HER1/HER2/HER3/HER4 ligands can enhance the activity of HER2, promote the tyrosine kinase domain phosphorylation, and induce BC progression through the signaling cascade mediated through the PI3K/AKT/mTOR and RAS-RAF-MEK-MAPK pathways to foster cell growth and proliferation.

Figure 3

Various conventional therapeutic agents (platinum drugs, anthracyclines, EGFR blockers, mTOR blockers, angiogenesis inhibitors, microtubule stabilizers, and PARP and PI3K-Akt inhibitors) were examined against the BCs. Many of them are FDA-approved drugs for BC therapy.