Leptin-cytokine crosstalk in breast cancer

Abstract

Despite accumulating evidence suggesting a positive correlation between leptin levels, obesity, post-menopause and breast cancer incidence, our current knowledge on the mechanisms involved in these relationships is still incomplete. Since the cloning of leptin in 1994 and its receptor (OB-R) 1 year later by Friedman's laboratory (Zhang et al., 1994) and Tartaglia et al. (Tartaglia et al., 1995), respectively, more than 22,000 papers related to leptin functions in several biological systems have been published (Pubmed, 2012). The ob gene product, leptin, is an important circulating signal for the regulation of body weight. Additionally, leptin plays critical roles in the regulation of glucose homeostasis, reproduction, growth and the immune response. Supporting evidence for leptin roles in cancer has been shown in more than 1000 published papers, with almost 300 papers related to breast cancer (Pubmed, 2012). Specific leptin-induced signaling pathways are involved in the increased levels of inflammatory, mitogenic and pro-angiogenic factors in breast cancer. In obesity, a mild inflammatory condition, deregulated secretion of proinflammatory cytokines and adipokines such as IL-1, IL-6, TNF-α and leptin from adipose tissue, inflammatory and cancer cells could contribute to the onset and progression of cancer. We used an in silico software program, Pathway Studio 9, and found 4587 references citing these various interactions. Functional crosstalk between leptin, IL-1 and Notch signaling (NILCO) found in breast cancer cells could represent the integration of developmental, proinflammatory and pro-angiogenic signals critical for leptin-induced breast cancer cell proliferation/migration, tumor angiogenesis and breast cancer stem cells (BCSCs). Remarkably, the inhibition of leptin signaling via leptin peptide receptor antagonists (LPrAs) significantly reduced the establishment and growth of syngeneic, xenograft and carcinogen-induced breast cancer and, simultaneously decreased the levels of VEGF/VEGFR2, IL-1 and Notch. Inhibition of leptin-cytokine crosstalk might serve as a preventative or adjuvant measure to target breast cancer, particularly in obese women. This review is intended to present an update analysis of leptin actions in breast cancer, highlighting its crosstalk to inflammatory cytokines and growth factors essential for tumor development, angiogenesis and potential role in BCSC.

Keywords: Breast cancer; Cytokines; Leptin; Leptin peptide receptor antagonist; NILCO; Obesity.

Fig. 1

Role of leptin and inflammatory cytokine crosstalk in breast cancer. Progression of breast cancer is closely related to leptin and the actions of angiogenic and inflammatory cytokines. Breast cancer cells and associate stroma express an array of inflammatory cytokines in a simultaneous manner. Adipose tissue expresses tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), which may cause obesity-related insulin resistance (Unkown, 2012; Kern et al., 2001). In primary breast cancer the expression of interleukin 1 (IL-1), IL-6 and TNF-α correlated to tumor associate macrophages (TAM) and VEGF (Ueno et al., 2000). Leptin crosstalk to cytokines in breast cancer is closely related to tumor progression (proliferation, migration and metastasis), which also impact on self-renewal of breast cancer stem cells and tumor angiogenesis (Guo et al., 2012a).

Fig. 2

In silico analysis of leptin-cytokine interactions in breast cancer. (A) Interaction networks between leptin and proteins involved in breast cancer were analyzed using Pathway studio program (Ariadine Genomics, MD). Detailed description of relationships detected is included in the supplementary material, (S1). (B) Relationships between leptin and main inflammatory cytokines [IL-6, IL-1, interleukin 17, (IL-17), TNF-α, and transforming growth factor beta, (TGF-β)] were imported and analyzed in terms of breast cancer. Detailed description of interactions is shown in supplementary material (S2).