Leptin signaling in breast cancer an overview of the book

Leptin is able to induce the growth of breast cancer cells through activation of the jakstat3, erk12, andor pi3k pathways, and can mediate angiogenesis by inducing the expression of vascular endothelial. A total of 794 cases and 805 matched controls were sequentially enrolled. Leptin upregulates notch14jag1dll4, while notch targets genes, hey2 and. N2 obesity is a risk factor for postmenopausal breast cancer and is associated with poor prognosis. Leptin receptor signaling supports cancer cell metabolism. Leptin promotes melanoma tumor growth in mice related to. Because leptin levels are elevated in obese individuals and excess body weight has been shown to increase breast cancer risk in postmenopausal women, attempts have. Here, we identify a role for the obesitycytokine leptin in sustaining aromatase inhibitor ai resistant growth and progression in breast cancer. We have shown previously that treatment with pegylated leptin peptide receptor antagonist 2 peglpra2 reduced the expression of vascular endothelial growth factor vegf, vascular endothelial growth factor receptor type 2 vegfr2 and growth of 4t1 breast cancer bc in syngeneic mice. Role of leptin and inflammatory cytokine crosstalk in breast cancer. Information regarding the effects of high leptin levels on leptin receptor expression and signaling is lacking. Expression of leptin and its receptors has been demonstrated to occur in breast cancer cell lines and in human primary breast carcinoma.

Leptin has been shown to increase the proliferation of human breast cancer cell lines expressing the leptin receptor obr, including mcf7, zr751, and the estrogenreceptor negative, htb26 cells. Recently, a novel mechanism has been proposed for the role of leptin in breast. Most importantly, obrl as well as other obr isoforms are overexpressed in breast cancer in comparison to normal mammary epithelium and benign mammary tumors 1, 7, 8. In breast cancer cells, lep has been implicated in promoting cell proliferation, migration and induction of angiogenesis, but the mechanisms by which it activates signaling by the long form of the. In silico analysis of leptincytokine interactions in breast cancer. Notch signaling and crosstalk with multiple signaling pathways have an essential role in breast cancer cell proliferation, migration, invasion, metastasis and even angiogenesis 25,41. Obesity in postmenopausal women is associated with increased breast cancer risk, development of more aggressive tumors and resistance to certain anti breast cancer treatments. Leptin acts on cell receptors in the arcuate nucleus of the hypothalamus. Further, we have also provided solid evidence sustaining a role for leptin signaling in breast cancer, by demonstrating that the inhibition of leptin signaling in vivo significantly delays the onset and reduces the growth of syngeneic, xenograft and carcinogenicinduced mammary tumors in mice gillespie et al. The purpose of this study was to characterize leptin receptor expression in response to leptin in breast cancer cells. Substantial epidemiological evidence has shown that excessive adiposity strongly influences risk, prognosis, and progression of various malignancies, including breast cancer. Leptin, an adipokine made in adipose tissue, may be a physiological link between cancer and obesity. A interaction networks between leptin and proteins involved in breast cancer were analyzed using pathway studio program ariadine genomics, md.

It has an association with progression and poor survival of. Obesity has been linked to higher rates of breast cancer as well as higher rates of endometrial, colon, kidney, gallbladder, and liver cancer, according to the centers for disease control cdc. Leptincytokine crosstalk in breast cancer sciencedirect. Epidemiological studies in some cases report elevated leptin levels in women with breast cancer and expression of the leptin receptor obr in breast tumors. Leptin is able to induce the growth of breast cancer cells through activation of the jakstat3, erk12, andor pi3k pathways, and can mediate angiogenesis by inducing the expression of vascular endothelial growth factor vegf. Overall, leptin resistance leads to dysregulated cytokine signaling, reduced. Leptin regulates various signaling pathways in many human cancers fig. An overview, abstract the adipocytederived peptide leptin acts through binding to specific membrane receptors, of which six isoforms obraf. Leptin promotes epithelialmesenchymal transition of breast. Towards better defining the role of leptin in breast cancer, herein we describe the identification of leptin regulated genes and proteins in hormone responsive mcf7 human breast cancer cells. The polymorphisms of leptin lep and leptin receptor lepr may be associated with breast cancer by regulator of adipose tissue mass and tumor cell growth. Recent data show that in pc and other cancer types the adipokine leptin can modulate notchrbpjk signaling, thereby, linking the pandemic obesity with cancer and chemoresistance. Akt silencing also exhibited the similar level of ecadherin and vimentin expression even in the presence of leptin treatment fig.

Leptin signaling enhances cell invasion and promotes the. An a to g transition mutation in codon 223 in exon 6 of. Signaling pathways induced by leptin during epithelial. Lepr has also been designated as cd295 cluster of differentiation 295. Leptinsignaling inhibition results in efficient anti. Role of leptin signaling in mammary tumor progression. This article presents an overview of the studies investigating the involvement of leptin and hyperactive leptin signaling network in cancer progression and strategies to inhibit leptin signaling. Leptin is an adipokine that is overexpressed in obese and overweight people.

It has an association with progression and poor survival of breast cancer. In the setting of obesity, a systemic chronic inflammatory response is characterized by alterations in the production and secretion of a wide variety of growth factors. In the present study, leptin increased the proliferation rate of two breast cancer cell lines in a dosedependent manner, indicating that leptin promotes the growth of breast cancer by stimulating cancer cell proliferation. Leptin is a hormone whose level increases drastically in the serum of obese patients. Leptin receptor expression and cell signaling in breast cancer. Leptininduced growth stimulation of breast cancer cells.

The direct involvement of leptin leptin receptor mediated signaling in the observed upregulation of exosomes release from breast cancer cells was demonstrated by using a selective inhibitor of leptin activity, the peptide ldfi, a small peptide of the wild type sequence of leptin binding site i, that we recently demonstrated to specifically. The relevance of leptin signaling in breast tumorigenesis is reinforced by the fact that the expression of obr mrna and protein has been documented in breast cancer biopsies. Given that obesity and diabetes have been associated with the development of numerous cancers 19, 20, leptin may act as a link between metabolic disorders and cancer. Leptin is known to regulate reproduction, bone homeostasis and immune signaling. Leptin, like insulin, appears to be a growth factor for breast cancer cells. This study aims to explore the effect of leptin on emt in breast cancer cells and the underlying mechanism. Pdf role of leptin in the pathogenesis of breast cancer.

Leptin promotes the growth of breast cancer by upregulating. A, mcf7 cells show increased phosphorylation of stat3 in response to leptin treatment. Cscs are cancer cells that exhibit resistance to chemo and radiotherapy and are associated with recurrence and metastasis. Leptin signaling inhibition results in efficient antitumor activity in estrogen receptor positive or negative breast cancer. Oncogenic role of dysregulated leptin signaling in the pathogenesis. There are several other factors such as insulin and her2 may be involved in the relationship between leptin. Table 1 influence of leptina signaling in imune cells. Leptin is also implicated in various physiological processers such as angiogenesis and hematopoiesis. The igf i signaling cascade has been shown to mediate breast cancer cell. In this study, we identify a role for the obesity cytokine leptin, which has been implicated previously in breast cancer development, as a determinant for the tumorpromoting activity of cancer associated fibroblasts caf in both wildtype wt and k303r mutant estrogen.

Activated fxr inhibits leptin signaling and counteracts tumor. Leptin plays an important role in breast cancer progression due to the biological processes it participates in, such as epithelialmesenchymal transition emt. Ijms free fulltext signaling pathways induced by leptin. Breast cancer cells and associate stroma express an array of inflammatory. Clearys studies by showing that leptin signaling deficient obob and dbdb mice do not develop mammary tumors. Lkb1mir34a axis and antagonizes the oncogenic actions of leptin in breast cancer. Get detailed information about breast cancer detection through tests such as mammograms, ultrasounds, other imaging tests and biopsies. The coexistence of deregulated insulin signaling in obesity has been. Leptin induces proliferation and notch expression in. Get the information you need to understand your breast cancer diagnosis with details on the various types of breast cancer, grading, hormone status, staging, and prognosis.

Leptinsignaling inhibition results in efficient antitumor. In this investigation, peglpra2 was used to evaluate whether the inhibition of leptin signaling has. Leptin modulates exosome biogenesis in breast cancer cells. Aug 30, 2011 leptin is a wellknown mediator of obesity.

In the context of breast cancer, leptin derived from local adipocytes is present at high concentrations within the mammary gland. Its administration decreases food intake and increases energy expenditure. Leptin is a hormone originally identified as the gene mutated in the obese mouse and its receptor lepr was identified as the gene mutated in the diabetic mouse. Leptin is able to induce the growth of breast cancer cells through. Breast cancer cells mcf7 were cultured, serum starved for 16 h, and treated with leptin 100 ngml for various intervals of time. Detailed description of relationships detected is included in the supplementary material, s1.

T1 leptin receptor expression and cell signaling in breast cancer. A novel and complex signaling crosstalk between leptin, notch and il1 notch, il1 and leptin crosstalk outcome, nilco seems to drive leptin induced oncogenic actions in breast cancer. Here we focused on the link between leptin and her2. Leptin can regulate endothelial cell proliferation and promote angiogenesis. Cell lysates were prepared and quantified for protein content. Mouse models to study leptin in breast cancer stem cells. Obesity has been implicated as a significant risk factor for development of pancreatic cancer. Notch, il1 and leptin are known proangiogenic inducing factors in breast cancer.

This tetrameric receptor ligand complex appears to be essential for signaling. Similar results were found in mdamb231derived mts from mice. Here, we present an overview of the role of leptin in breast cancer. Leptin is a polypeptide synthesized and secreted by adipocytes see the leptin chapters in endocrine, cancer, ingestive, and gastrointestinal peptides sections of the book. Leptin as a mediator of tumorstromal interactions promotes. Current standardized therapy for breast cancer, used often in. Serum leptin higher in breast cancer patients than in patients with benign breast disease or in healthy controls.

Time 0 represents the absence of leptin or untreated cells u. Leptin signaling inhibition results in efficient antitumor activity in estrogen receptor positive or negative breast cancer ruben rene gonzalez 1,2,3, amber watters 1, yanbo xu 1. This article presents an overview of the studies investigating the involvement of leptin and hyperactive leptin signaling network in cancer progression and strategies to inhibit leptin signaling in cancer. Using as experimental models mcf7 breast cancer cells surviving longterm treatment with the ai. Relation between leptin levels and liver fibrosis in humans is conflicting with some studies showing a significantly higher leptin levels in individuals with nonalcoholic. Pancreatic adenocarcinoma pa is an aggressive cancer.

There are still many gaps to fill in the field of leptin signaling in breast cancer, especially the molecular mechanisms of leptin signalingmediated regulation of bcsc. Novel opportunities could emerge from the discovery of leptin crosstalk with inflammatory and angiogenic cytokines i. Both the obese and diabetic mice exhibit early onset obesity and have been extensively studied to delineate mechanisms of obesity and associated morbidities. Leptin induced tumor cell growth and inhibited apoptosis in papillary thyroid cancer ptc cells.

Leptin, a 16 kda polypeptide hormone, implicated in various physiological processes, exerts its action through the leptin receptor, a member of the class i cytokine receptor family. Some of these effects might be mediated by obesity hormone leptin, acting independently or modulating other signaling pathways. Leptin s effects will be abrogated by the inhibitor of leptin signaling, ionplpra2. Binding of leptin to its receptor induces activation. Nilco could represent the integration of developmental, proinflammatory, and proangiogenic events critical for leptin induced cell proliferationmigration. Obesity represents a risk factor for breast cancer development and therapy resistance, but the molecular players underling these links are unclear. The multifaceted mechanism of leptin signaling within tumor. Emt consists of a series of orchestrated events in which cell. Obesity and cancer fact sheet national cancer institute. Research indicates that obesity may worsen several aspects of cancer survivorship, including quality of life, cancer recurrence, cancer progression, and prognosis survival 37, 38. Finally, we will summarize new data regarding the obesity paradox based on. Its location is the cell membrane, and it has extracellular, transmembrane and intracellular sections protein regions. Modulation of the leptin receptor mediates tumor growth and. Evidence indicates leptin plays an important role in breast cancer development and progression.

N2 obesity is considered a risk factor for many cancers, including breast cancer. Obesity confers risks to cancer development and progression but the mechanisms underlying these risks remain unclear. In addition, leptin can stimulate mitogenic and angiogenic processes in peripheral organs. Immunohistochemistry analysis revealed that the levels of leptin, obr, human vegf, vegfr2 or flk1, pcna, human il1r ti and cyclin d 1 were significantly lower in mcf7 tumors from mice treated with peglpra2 than in tumors from scpegtreated controls figure 2a. T1 effects of leptin on human breast cancer cell lines in relationship to estrogen receptor and her2 status. Effects of leptin on human breast cancer cell lines in.

Interestingly, women with breast cancer present high levels of leptin and of its receptor obr. Linkage between obesity leptin and breast cancer manar fayiz. It develops in a way that causes almost no detectable symptoms, which leads to a rapid progression and a short survival rate. Most of the evidence about obesity in cancer survivors comes from people who were diagnosed with breast, prostate, or colorectal cancer. Moreover, the progeny from obob or dbdb mice crossed with mttvtgf. Leptin lepr signaling regulate body fat via activation of brain. Obesity represents a risk factor for certain types of cancer.

Rene gonzalez r, watters a, xu y, singh up, mann dr, rueda br, penichet ml. Leptin receptor gln223arg polymorphism and breast cancer risk. These results indicated that leptininduced il8 secretion through pi3kakt signal pathway might be essential for emt in human breast cancer cells. Lepr functions as a receptor for the fat cellspecific hormone leptin. Emt consists of a series of orchestrated events in which. Leptin from greek leptos, thin is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate energy balance by inhibiting hunger, which in turn diminishes fat storage in adipocytes. The nuclear farnesoid x receptorfxr seems to exert an oncosuppressive role in different tumors, including breast cancer. Evidence of an autocrine role for leptin and leptin receptor in human breast cancer leptin attenuates the antiestrogen effect of tamoxifen in breast cancer dietary flaxseed oil reduces adipocyte size, adipose monocyte chemoattractant protein1 levels and tcell infiltration in obese, insulinresistant rats. Leptin in over expressed in colorectal cancer, and the expression increases gradually across the spectrum from normal mucosa, simple adenoma with low grade dysplasia, adenoma with high grade dysplasia to adenocarcinoma. Breast cancer, colorectal cancer, hepatocellular cancer, leptin, thyroid cancer i ntroduction leptin is a 167aminoacid peptide hormone produced predominantly by adipocytes and to a less extent by stomach, skeletal tissue and placenta, was discovered by friedman et al.

A recent metaanalysis conducted by chinese researchers also concluded that leptin levels play such a a role in breast cancer development that they. Jan 26, 2007 leptin is a multifunctional hormone produced mainly by the adipose tissue and involved in the regulation of food intake and energy balance. Leptin signaling inhibition results in efficient antitumor activity in estrogen receptor positive or negative breast cancer ruben rene gonzalez 1,2,3, amber watters 1, yanbo xu 1, udai p singh 4, david r mann 5. In addition, leptin induces transactivation of erbb2.

Oncogenic role and therapeutic target of leptin signaling. Leptinsignaling pathways as therapeutic targets in cancer. An overview leptin, the product of the obesity ob gene, is a circulating peptide hormone acting as a regulator of food intake via hypothalamic. Conditioned media cm from cancer associated fibroblasts and breast adipocytes significantly increased mammosphere formation in breast cancer cells and depletion of leptin from cm. An overview, abstract the adipocytederived peptide leptin acts through binding to specific membrane receptors, of which six isoforms obraf have been identified up to now. Leptin and its receptor are overexpressed in breast cancer, especially in highgrade tumors. Several leptin induced signaling pathways and factors have been linked to the proliferation of breast, endometrial and pancreatic cancer cells12,16,36,37. Targeting notch degradation system provides promise for. Breast cancer is the most common cancer diagnosed among women worldwide. Leptin, a hormone predominantly produced by adipocytes, is elevated in the obese state. Leptin acts as a growth hormone in the mcf7 breast cancer cell line. Leptin receptor, also known as lepr or obr, is a type i cytokine receptor, a protein that in humans is encoded by the lepr gene.

Leptininduced jakstat signaling and cancer growth mdpi. Leptin treatment promoted breast cancer cell proliferation. Acetylcoa carboxylase 1dependent protein acetylation. Leptin signaling pathway homo sapiens wikipathways. The role of notch signaling and leptinnotch crosstalk in. Oct 21, 2016 leptin, a key adipokine secreted from adipocytes, shapes the tumor microenvironment, potentiates the migration of breast cancer cells and angiogenesis, and is also involved in emt. The prevalence of obesity has been steadily increasing over the past few decades in several developed and developing countries, with resultant hazardous health implications.