Synergy of leptin/STAT3 with HER2 receptor induces tamoxifen resistance in breast cancer cells through regulation of apoptosis-related genes

Papanikolaou, Vassilis; Stefanou, Nikolaos; Dubos, Stephanie; Papathanasiou, Ioanna V.; Palianopoulou, Maria; Valiakou, Vaia; Tsezou, Aspasia

doi:10.1007/s13402-014-0213-5

Cited by 21 publications

(13 citation statements)

References 69 publications

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“…Leptin treatment reduced this resistance and this effect was associated with decreased STAT3 regulation of apoptosis-related genes [108]. In ER-negative breast cancer cells, there may be an alternate pathway for mediating the effects of leptin not only via the ObR -STAT3 pathway, but also by induction of the oncogene SK1-ERK1/2-mediated pathway [109].…”

Section: The Role Of Leptin In the Tumour Microenvironmentmentioning

confidence: 99%

Emerging Concepts Linking Obesity with the Hallmarks of Cancer

Donohoe

Lysaght

O'Sullivan

et al. 2017

Trends in Endocrinology & Metabolism

102

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Section: The Role Of Leptin In the Tumour Microenvironmentmentioning

confidence: 99%

Emerging Concepts Linking Obesity with the Hallmarks of Cancer

Donohoe

Lysaght

O'Sullivan

et al. 2017

Trends in Endocrinology & Metabolism

102

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“…In this study, normal human breast epithelium (184.a1 line) and normal mouse mammary epithelial cells (NMuMG) were used. Furthermore, studies found reduced sensitivity to antiestrogen tamoxifen after the administration of leptin to breast cancer cells (MDA-MB-231, MCF-7, and MCF-7/HER2 cell-lines), especially HER2-overexpressing cells [138], [140].…”

Section: Breast Cancer and Her2 In Obesity: In Vitro And In Vivo Obsementioning

confidence: 99%

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

Ray

2017

Hormone Molecular Biology and Clinical Investigation

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Abstract:Obesity is associated with the risk of several health disorders including certain cancers. Among obesity-related cancers, postmenopausal breast carcinoma is a well-studied one. Apart from an increase in certain types of lipids in obesity, excess adipose tissue releases many hormone-like cytokines/adipokines, which are usually pro-inflammatory in nature. Leptin is one of such adipokines and significantly linked with the intracellular signaling pathways of other growth factors such as insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2). In general, HER2 is overexpressed in roughly 30% of breast carcinomas; its presence indicates aggressive tumor behavior. Conversely, HER2 has certain effects in normal conditions such as differentiation of preadipocytes, cardiovascular health and vitamin D metabolism. HER2 has no known endogenous ligand, but it may form dimers with other three members of the epidermal growth factor receptor (EGFR) family and can activate downstream signaling pathways. Furthermore, HER2 is intimately connected with several enzymes, e.g. fatty acid synthase (FASN), phosphatidylinositol 3-kinase (PI3K), AKT and mechanistic target of rapamycin (mTOR), all of which play significant regulatory roles in lipogenic pathways or lipid metabolism. In obesity-related carcinogenesis, characteristics like insulin resistance and elevated IGF-1 are commonly observed. Both IGF-1 and leptin can modulate EGFR and HER2 signaling pathways. Although clinical studies have shown mixed results, the behavior of HER2+ tumor cells including HER2 levels can be altered by several factors such as obesity, leptin and fatty acids. A precise knowledge is useful in new therapeutic approaches against HER+ tumors.

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“…The obesity-related adipokine leptin has been well characterized as a growth factor for breast cancer and has been recently proposed to decrease sensitivity to tamoxifen in vitro. It has been demonstrated that leptin treatment interferes with the antagonistic effects of tamoxifen in ERα-positive breast cancer cells [32,33] and the synergy between the leptin/Ob-R/STAT3 signaling pathway with the HER2 receptor induces tamoxifen resistance in breast cancer cells through differential regulation of apoptosis-related genes [35]. Interestingly, ObR knockdown significantly enhanced the inhibitory effects of tamoxifen on the proliferation and survival of tamoxifen-resistant cells [34].…”

Section: Discussionmentioning

confidence: 99%

“…Of note, leptin is able to shape the tumor microenvironment by inducing multiple concurrent events, for example, a promotion of angiogenesis and a sustained recruitment of monocytes and macrophages, which in turn secrete VEGF (vascular endothelial growth factor) and proinflammatory cytokines [29][30][31]. However, only a few studies have indicated a role of this adipokine in endocrine resistance, such as tamoxifen resistance [26,[32][33][34][35][36][37], and so far, its involvement in AI therapy resistance has not yet been investigated. Here, we present data showing the involvement of the leptin-mediated signaling pathway in the development of AI therapy resistance, thereby suggesting how blocking leptin signaling could be further exploited for clinical utility in breast cancer resistant settings, especially for obese patients.…”

Section: Introductionmentioning

confidence: 99%

Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages

et al. 2020

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Obesity represents a risk factor for breast cancer development and therapy resistance, but the molecular players underling these links are unclear. Here, we identify a role for the obesity-cytokine leptin in sustaining aromatase inhibitor (AI) resistant growth and progression in breast cancer. Using as experimental models MCF-7 breast cancer cells surviving long-term treatment with the AI anastrozole (AnaR) and Ana-sensitive counterparts, we found that AnaR cells expressed higher levels of leptin and its receptors (ObR) along with a constitutive activation of downstream effectors. Accordingly, leptin signaling inhibition reduced only AnaR cell growth and motility, highlighting the existence of an autocrine loop in mechanisms governing drug-resistant phenotypes. In agreement with ObR overexpression, increasing doses of leptin were able to stimulate to a greater extent growth and migration in AnaR than sensitive cells. Moreover, leptin contributed to enhanced crosstalk between AnaR cells and macrophages within the tumor microenvironment. Indeed, AnaR, through leptin secretion, modulated macrophage profiles and increased macrophage motility through CXCR4 signaling, as evidenced by RNA-sequencing, real-time PCR, and immunoblotting. Reciprocally, activated macrophages increased AnaR cell growth and motility in coculture systems. In conclusion, acquired AI resistance is accompanied by the development of a leptin-driven phenotype, highlighting the potential clinical benefit of targeting this cytokine network in hormone-resistant breast cancers, especially in obese women.

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Synergy of leptin/STAT3 with HER2 receptor induces tamoxifen resistance in breast cancer cells through regulation of apoptosis-related genes

Abstract: Our study provides novel evidence indicating that synergy between the leptin/Ob-Rb/STAT3 signalling pathway and the HER2 receptor protects tamoxifen-treated HER2 over-expressing cells from the inhibitory effect of tamoxifen through differential regulation of apoptosis-related genes.

Cited by 21 publications

References 69 publications

Emerging Concepts Linking Obesity with the Hallmarks of Cancer

Emerging Concepts Linking Obesity with the Hallmarks of Cancer

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages

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