Leptin deficiency suppresses MMTV-Wnt-1 mammary tumor growth in obese mice and abrogates tumor initiating cell survival

Abstract

Obesity increases both the risk and mortality associated with many types of cancer including that of the breast. In mice, obesity increases both incidence of spontaneous tumors and burden of transplanted tumors. Our findings identify leptin, an adipose secreted cytokine, in promoting increased mammary tumor burden in obese mice and provide a link between this adipokine and cancer. Using a transplantable tumor that develops spontaneously in the Murine Mammary Tumor Virus (MMTV)-Wnt-1 transgenic mice, we show that tumors transplanted into obese leptin-receptor deficient (db/db) mice grow to 8-times the volume of tumors transplanted into lean wild type (WT) mice. However, tumor outgrowth and overall tumor burden is reduced in obese, leptin-deficient (ob/ob) mice. The residual tumors in ob/ob mice contain fewer undifferentiated tumor cells (keratin 6 immunopositive) compared to WT or db/db mice. Further, tumors in ob/ob mice contain fewer cells expressing phosphorylated Akt, a growth promoting kinase activated by the leptin receptor (LepRb), compared to WT and db/db mice. In vivo limiting dilution analysis of residual tumors from ob/ob mice indicated reduced tumor initiating activity suggesting fewer cancer stem cells (CSCs). The tumor cell populations reduced by leptin-deficiency were identified by fluorescence activated cell sorting and found to express LepRb. Finally, LepRb expressing tumor cells exhibit stem cell characteristics based on the ability to form tumorspheres in vitro and leptin promotes their survival. These studies provide critical new insight on the role of leptin in tumor growth and implicate LepRb as a CSC target.

Leptin-induced Epithelial-Mesenchymal Transition in Breast Cancer Cells Requires β-Catenin Activation via Akt/GSK3- and MTA1/Wnt1 Protein-dependent Pathways

“…Also, xenografts of MMTV-Wnt1 tumors transplanted in diet-induced obese mice grow faster as compared with lean counterparts (17). Consistent with the important role of leptin in breast tumorigenesis, xenografts of MMTV-Wnt1 cancer cells transplanted into leptin-deficient obese (Ob/Ob) mice display stunted growth (18). Cellular studies from our laboratory and others have shown that leptin signaling regulates various molecules involved in proliferation, adhesion, invasion, migration, inflammation, and angiogenesis, such as cyclin D1, survivin, ␤3 integrin, interleukin-1 (IL-1), IL-1 receptor, vascular endothelial growth factor, and its receptor type 2 in breast carcinogenesis (6, 19 -25).…”

Adipose tissue, obesity and adipokines: role in cancer promotion

“…The role of leptin in tumor growth is demonstrated via mice cancer models. More specifically, MMTV-Wnt-1 mice, a model of mammary tumor growth, that are obese but leptin deficient, have suppressed mammary tumor growth and decreased tumor cell survival compared with those that are leptin sufficient [36]. Leptin acts as a growth hormone in the MCF-7 breast cancer cell line through an increase in aromatase via ERK and STAT pathways [37], as well as enhanced DNA binding of the AP-1 transcription factor [37].…”

Crown-like Structures in Breast Adipose Tissue from Normal Weight Women: Important Impact

“…Under physiologic conditions, leptin serves an anorexigenic function. It also functions to stimulate proinflammatory pathways in monocytes and macrophages and has been shown to promote tumor growth in mammary tumor systems (7). In contrast, synthesis and secretion of adiponectin, an anti-inflammatory and proapoptotic adipokine, is often downregulated in obesity (6).…”