The Multifaceted Mechanism of Leptin Signaling within Tumor Microenvironment in Driving Breast Cancer Growth and Progression

Adipokines represent likely candidates to mediate the increased breast cancer risk and the enhanced progression associated with obesity. Other contributors to obesity-related cancer progression are insulin/IGF-1 pathways and hormones. Among these, the adipokine leptin is the most intensively studied in both metabolism in general and in cancer due to the fact that leptin levels increase in proportion of fat mass. Leptin is primarily synthesized from adipocytes but it is also produced by other cells including fibroblasts. In this latter case, it has been well demonstrated how cancer-associated fibroblasts express leptin receptor and secrete leptin, which sustains a short autocrine loop and is able to target tumor epithelial cells enhancing breast cancer cell motility and invasiveness. In addition, it has been reported that leptin may induce breast cancer to undergo a transition from epithelial to spindle-like mesenchymal morphology, activating the signaling pathways devoted to the EMT. Thus, it emerges how leptin may play a crucial role in mediating malignant cell and tumor microenvironment interactions. Here, we present an overview of the role of leptin in breast cancer, covering the following topics: (1) leptin as an amplifier of estrogen signaling in tumor epithelial cells contributing to the promotion of carcinogenesis; (2) leptin as a crucial player in mediating tumor-stroma interaction and influencing EMT-linked mechanisms, that may sustain breast cancer growth and progression; (3) leptin and leptin receptor targeting as novel therapeutic strategies for breast cancer treatment.

[1]  M. Taouis,et al.  Identification of the hydrophobic strand in the A-B loop of leptin as major binding site III: implications for large-scale preparation of potent recombinant human and ovine leptin antagonists. , 2005, The Biochemical journal.

[2]  Shanchun Guo,et al.  Notch, IL-1 and Leptin Crosstalk Outcome (NILCO) Is Critical for Leptin-Induced Proliferation, Migration and VEGF/VEGFR-2 Expression in Breast Cancer , 2011, PloS one.

[3]  Candida N. Perera,et al.  Leptin-regulated gene expression in MCF-7 breast cancer cells: mechanistic insights into leptin-regulated mammary tumor growth and progression. , 2008, The Journal of endocrinology.

[4]  L. Tessitore,et al.  Leptin expression in colorectal and breast cancer patients. , 2000, International journal of molecular medicine.

[5]  C. Giordano,et al.  Leptin increases HER2 protein levels through a STAT3‐mediated up‐regulation of Hsp90 in breast cancer cells , 2013, Molecular oncology.

[6]  Xin Hu,et al.  Leptin--a growth factor in normal and malignant breast cells and for normal mammary gland development. , 2003, Journal of the National Cancer Institute.

[7]  Hao Song,et al.  Upregulation of survivin by leptin/STAT3 signaling in MCF-7 cells. , 2008, Biochemical and biophysical research communications.

[8]  J. Grande,et al.  Genetically Obese MMTV-TGF-α/LepobLepob Female Mice do not Develop Mammary Tumors , 2003, Breast Cancer Research and Treatment.

[9]  D. Sharma,et al.  Leptin-induced Epithelial-Mesenchymal Transition in Breast Cancer Cells Requires β-Catenin Activation via Akt/GSK3- and MTA1/Wnt1 Protein-dependent Pathways* , 2012, The Journal of Biological Chemistry.

[10]  Alexander Quarshie,et al.  Obesity induced a leptin‐Notch signaling axis in breast cancer , 2014, International journal of cancer.

[11]  P. Mahadevan,et al.  An overview , 2007, Journal of Biosciences.

[12]  A. Gertler,et al.  Large-scale preparation and characterization of non-pegylated and pegylated superactive ovine leptin antagonist. , 2012, Protein expression and purification.

[13]  D. Sharma,et al.  Multifaceted Leptin Network: The Molecular Connection Between Obesity and Breast Cancer , 2013, Journal of Mammary Gland Biology and Neoplasia.

[14]  E. Simpson,et al.  Subcellular localization of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 provides a link between obesity and breast cancer in postmenopausal women. , 2009, Cancer research.

[15]  R. Ahima,et al.  Leptin signaling , 2014, F1000prime reports.

[16]  K. Machida,et al.  Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells , 2011, Proceedings of the National Academy of Sciences.

[17]  D. Newgreen,et al.  Induction of epithelial to mesenchymal transition in PMC42-LA human breast carcinoma cells by carcinoma-associated fibroblast secreted factors , 2007, Breast Cancer Research.

[18]  Olivier De Wever,et al.  Role of tissue stroma in cancer cell invasion , 2003, The Journal of pathology.

[19]  조남훈,et al.  Stromal fibroblasts from the interface zone of human breast carcinomas induce an epithelial-mesenchymal transition-like state in breast cancer cells in vitro. , 2010 .

[20]  L. Tessitore,et al.  Adipocyte expression and circulating levels of leptin increase in both gynaecological and breast cancer patients. , 2004, International journal of oncology.

[21]  A. Russo,et al.  Increased Expression of Leptin and the Leptin Receptor as a Marker of Breast Cancer Progression: Possible Role of Obesity-Related Stimuli , 2006, Clinical Cancer Research.

[22]  J. Rich,et al.  Leptin receptor maintains cancer stem-like properties in triple negative breast cancer cells. , 2013, Endocrine-related cancer.

[23]  R. Hoffmann,et al.  Development of a pharmacologically improved peptide agonist of the leptin receptor. , 2008, Biochimica et biophysica acta.

[24]  A. Ray,et al.  Effects of leptin on human breast cancer cell lines in relationship to estrogen receptor and HER2 status. , 2007, International journal of oncology.

[25]  Xue-mei Ma,et al.  Regulation of estrogen receptors α and β in human breast carcinoma by exogenous leptin in nude mouse xenograft model , 2010 .

[26]  S. Catalano,et al.  The multifactorial role of leptin in driving the breast cancer microenvironment , 2012, Nature Reviews Endocrinology.

[27]  Dipali Sharma,et al.  Leptin-induced Growth Stimulation of Breast Cancer Cells Involves Recruitment of Histone Acetyltransferases and Mediator Complex to CYCLIN D1 Promoter via Activation of Stat3* , 2007, Journal of Biological Chemistry.

[28]  C. Giordano,et al.  Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor alpha in MCF-7 cells. , 2004, The Journal of biological chemistry.

[29]  Annette Meeson,et al.  Epithelial-to-mesenchymal transition: what is the impact on breast cancer stem cells and drug resistance. , 2014, Cancer treatment reviews.

[30]  J. Peyrat,et al.  Identification of leptin receptors in human breast cancer: functional activity in the T47-D breast cancer cell line , 2002, Molecular and Cellular Endocrinology.

[31]  C. Giordano,et al.  Leptin Enhances, via AP-1, Expression of Aromatase in the MCF-7 Cell Line* , 2003, Journal of Biological Chemistry.

[32]  D. Noh,et al.  Leptin as a Potential Target for Estrogen Receptor-Positive Breast Cancer , 2013, Journal of breast cancer.

[33]  M. Vasson,et al.  Leptin and leptin receptor involvement in cancer development: a study on human primary breast carcinoma. , 2008, Oncology reports.

[34]  D. Mcfadden,et al.  Differential effects of leptin on cancer in vitro. , 2003, The Journal of surgical research.

[35]  H. Nagawa,et al.  Leptin augments proliferation of breast cancer cells via transactivation of HER2. , 2008, The Journal of surgical research.

[36]  O. Livnah,et al.  Comparison of R128Q mutations in human, ovine, and chicken leptins. , 2002, General and comparative endocrinology.

[37]  H. Moses,et al.  Stromal fibroblasts in cancer initiation and progression , 2004, Nature.

[38]  I. Kovalszky,et al.  Efficacy of a leptin receptor antagonist peptide in a mouse model of triple-negative breast cancer. , 2011, European journal of cancer.

[39]  S. Chua,et al.  Tumorigenesis and Neoplastic Progression Leptin Receptor Signaling Supports Cancer Cell Metabolism through Suppression of Mitochondrial Respiration in Vivo , 2010 .

[40]  R. Franco,et al.  Cellular and molecular crosstalk between leptin receptor and estrogen receptor-{alpha} in breast cancer: molecular basis for a novel therapeutic setting. , 2010, Endocrine-related cancer.

[41]  C. Giordano,et al.  Leptin Induces, via ERK1/ERK2 Signal, Functional Activation of Estrogen Receptor α in MCF-7 Cells* , 2004, Journal of Biological Chemistry.

[42]  Orly Dym,et al.  Subcloning, Expression, Purification, and Characterization of Recombinant Human Leptin-binding Domain* , 2002, The Journal of Biological Chemistry.

[43]  E. Surmacz,et al.  Leptin Interferes with the Effects of the Antiestrogen ICI 182,780 in MCF-7 Breast Cancer Cells , 2004, Clinical Cancer Research.

[44]  H. Nagawa,et al.  Enhanced Expression of Leptin and Leptin Receptor (OB-R) in Human Breast Cancer , 2004, Clinical Cancer Research.

[45]  A. Giordano,et al.  Leptin signaling in breast cancer: An overview , 2008, Journal of cellular biochemistry.

[46]  Z. Halpern,et al.  Development and Characterization of High Affinity Leptins and Leptin Antagonists* , 2010, The Journal of Biological Chemistry.

[47]  E. Gussakovsky,et al.  Large-scale preparation of biologically active mouse and rat leptins and their L39A/D40A/F41A muteins which act as potent antagonists. , 2006, Protein expression and purification.

[48]  A. Gertler.  Development of leptin antagonists and their potential use in experimental biology and medicine , 2006, Trends in Endocrinology & Metabolism.

[49]  C. Giordano,et al.  Evidences that leptin up-regulates E-cadherin expression in breast cancer: effects on tumor growth and progression. , 2007, Cancer research.

[50]  S. Weitsman,et al.  Leptin regulation of aromatase activity in adipose stromal cells from regularly cycling women. , 1999, Ginekologia polska.

[51]  G. Sweeney.  Leptin signalling. , 2002, Cellular signalling.

[52]  J. Grande,et al.  Leptin receptor-deficient MMTV-TGF-alpha/Lepr(db)Lepr(db) female mice do not develop oncogene-induced mammary tumors. , 2004, Experimental biology and medicine.

[53]  G. Matarese,et al.  Identification of a monoclonal antibody against the leptin receptor that acts as an antagonist and blocks human monocyte and T cell activation. , 2006, Journal of immunological methods.

[54]  Y. Shang,et al.  Molecular Mechanisms Involved in the Growth Stimulation of Breast Cancer Cells by Leptin , 2004, Cancer Research.

[55]  P. Leavis,et al.  A peptide derived from the human leptin molecule is a potent inhibitor of the leptin receptor function in rabbit endometrial cells , 2003, Endocrine.

[56]  M. Dieudonné,et al.  Leptin mediates a proliferative response in human MCF7 breast cancer cells. , 2002, Biochemical and biophysical research communications.

[57]  P. Chieffi,et al.  Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis. , 2006, The Journal of clinical investigation.

[58]  Charlotte Kuperwasser,et al.  Stroma in breast development and disease. , 2010, Seminars in cell & developmental biology.

[59]  M. Dieudonné,et al.  Direct in vitro effects of androgens and estrogens on ob gene expression and leptin secretion in human adipose tissue , 2002, Endocrine.

[60]  Shanchun Guo,et al.  Oncogenic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells. , 2012, Biochimica et biophysica acta.

[61]  M. C. Archer,et al.  Susceptibility of lean and obese Zucker rats to tumorigenesis induced by N-methyl-N-nitrosourea. , 2001, Cancer letters.

[62]  Yu-mei Feng,et al.  Cancer-associated fibroblasts induce epithelial–mesenchymal transition of breast cancer cells through paracrine TGF-β signalling , 2013, British Journal of Cancer.

[63]  I. Barone,et al.  Therapeutic potential of leptin receptor modulators. , 2014, European journal of medicinal chemistry.

[64]  S. Lovas,et al.  Peptide‐based leptin receptor antagonists for cancer treatment and appetite regulation , 2011, Biopolymers.

[65]  J. Rich,et al.  Leptin deficiency suppresses MMTV-Wnt-1 mammary tumor growth in obese mice and abrogates tumor initiating cell survival. , 2011, Endocrine-related cancer.

[66]  R. Considine,et al.  Serum immunoreactive-leptin concentrations in normal-weight and obese humans. , 1996, The New England journal of medicine.

[67]  E. Ravussin,et al.  Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects , 1995, Nature Medicine.

[68]  J. Grosclaude,et al.  Mapping leptin-interacting sites in recombinant leptin-binding domain (LBD) subcloned from chicken leptin receptor. , 2005, The Biochemical journal.

[69]  J. Grande,et al.  Leptin Receptor-Deficient MMTV-TGF-α/Leprdb Leprdb Female Mice Do Not Develop Oncogene-Induced Mammary Tumors , 2004 .

[70]  S. Catalano,et al.  In vivo and in vitro evidence that PPARγ ligands are antagonists of leptin signaling in breast cancer. , 2011, The American journal of pathology.

[71]  Lily Yang,et al.  Survivin upregulation, dependent on leptin-EGFR-Notch1 axis, is essential for leptin-induced migration of breast carcinoma cells. , 2011, Endocrine-related cancer.

[72]  C. Giordano,et al.  Leptin mediates tumor-stromal interactions that promote the invasive growth of breast cancer cells. , 2012, Cancer research.

[73]  N. Cho,et al.  Stromal fibroblasts from the interface zone of human breast carcinomas induce an epithelial–mesenchymal transition-like state in breast cancer cells in vitro , 2010, Journal of Cell Science.

[74]  A. Aboussekhra.  Role of cancer-associated fibroblasts in breast cancer development and prognosis. , 2011, The International journal of developmental biology.

[75]  K. Yasuda,et al.  Leptin and high glucose stimulate cell proliferation in MCF-7 human breast cancer cells: reciprocal involvement of PKC-alpha and PPAR expression. , 2002, Biochimica et biophysica acta.

[76]  J. Grande,et al.  Genetically obese MMTV-TGF-alpha/Lep(ob)Lep(ob) female mice do not develop mammary tumors. , 2003, Breast cancer research and treatment.

[77]  Xue-mei Ma,et al.  Regulation of estrogen receptors alpha and beta in human breast carcinoma by exogenous leptin in nude mouse xenograft model. , 2010, Chinese medical journal.

[78]  J. Schölmerich,et al.  Mechanisms of Disease: adipokines and breast cancer—endocrine and paracrine mechanisms that connect adiposity and breast cancer , 2007, Nature Clinical Practice Endocrinology &Metabolism.

[79]  V. De Rosa,et al.  Leptin increase in multiple sclerosis associates with reduced number of CD4(+)CD25+ regulatory T cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[80]  M. Penichet,et al.  Leptin-signaling inhibition results in efficient anti-tumor activity in estrogen receptor positive or negative breast cancer , 2009, Breast Cancer Research.

[81]  T. Funahashi,et al.  High expression of leptin receptor mRNA in breast cancer tissue predicts poor prognosis for patients with high, but not low, serum leptin levels , 2006, International journal of cancer.