Leptin Augments Proliferation of Breast Cancer Cells via Transactivation of HER2

Soma, Daisuke; Kitayama, Joji; Yamashita, Hiroharu; Miyato, Hideyo; Itō, Makoto; Nagawa, Hirokazu

doi:10.1016/j.jss.2007.10.012

Cited by 69 publications

(62 citation statements)

References 55 publications

(51 reference statements)

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“…In MCF-7 cells, which contain relatively high levels of ObR [32] and moderate levels of HER2, high physiological doses of leptin can induce HER2 tyrosine phosphorylation. Similar transactivation was recently described in SK-BR-3 cells [29]. In the case of MCF-7 cells, we show that leptin-dependent stimulation of HER2 Expression of the leptin/ObR system in HER2-positive and -negative breast cancer Figure 4 Expression of the leptin/ObR system in HER2-positive and -negative breast cancer.…”

Section: Discussionsupporting

confidence: 88%

“…In the context of the most aggressive breast cancer, it is important that leptin could crosstalk with HER2 either through ObR, HER1, and JAK2 [22,29].…”

Section: Discussionmentioning

confidence: 99%

“…In the case of MCF-7 cells, we show that leptin-dependent stimulation of HER2 Expression of the leptin/ObR system in HER2-positive and -negative breast cancer Figure 4 Expression of the leptin/ObR system in HER2-positive and -negative breast cancer. [29].…”

Section: Discussionmentioning

confidence: 99%

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HER2/Leptin Crosstalk in Breast Cancer

Surmacz¹

2009

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information , 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY) 01-09-2009 REPORT TYPE Final DATES COVERED (From -To)September 1 DISTRIBUTION / AVAILABILITY STATEMENTApproved for public release; distribution unlimited SUPPLEMENTARY NOTES ABSTRACTObesity in postmenopausal women is associated with increased breast cancer risk, development of more aggressive tumors and resistance to certain anti-breast cancer treatments. These effects might be mediated by obesity hormone leptin. Here we investigated if leptin can transactivate the oncogenic receptor HER2 and interfere with the activity of anti-HER2 antibody.We found that HER2 and the leptin receptor (ObR) are coexpressed in several studied breast cancer cell lines. In MCF-7 cells, HER2 physically interacted with ObR and leptin treatment increased HER2 phosphorylation on Tyr 1248. Furthermore, leptin reduced the efficacy of anti-HER2 drug Herceptin. Studies of human breast cancers revealed that the presence of leptin correlated with ObR, and the whole leptin system was coexpressed with HER2 in ~50% of all tumors. Thus, coexpression of HER2 and the leptin/ObR system might contribute to enhanced HER2 activity and reduced sensitivity to anti-HER2 treatments. IntroductionObesity has been shown to be associated with increased breast cancer risk in postmenopausal women, development of more aggressive breast tumors and resistance to certain anti-breast cancer treatments [1]. The molecular mechanisms of these effects are still not clear. Recent data suggested that excess body weight could promote breast cancer through increased production of an adipocyte-derived hormone leptin [2]. The purpose of this work was to assess whether leptin can transactivate the oncogenic receptor HER2 in breast cancer cells, and if leptin/HER2 interaction could occur in vivo, in human breast cancer. Consequently, the objectives of this proposal were: 1) To examine the expression of leptin receptors (ObRl and ObRs) in anonymized HER2-positive breast tumor biopsies; 2) To establish correlations between each leptin, ObRl and ObRs and tumor characteristics; 3) To examine in breast cancer cell models if activation of the leptin receptor can induce HER2 phosphorylation and...

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Section: Discussionsupporting

confidence: 88%

“…In the context of the most aggressive breast cancer, it is important that leptin could crosstalk with HER2 either through ObR, HER1, and JAK2 [22,29].…”

Section: Discussionmentioning

confidence: 99%

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HER2/Leptin Crosstalk in Breast Cancer

Surmacz¹

2009

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“…In close agreement with this hypothesis, several lines of evidence support the role of leptin in the neoplastic processes [6][7][8][9]. Moreover, this is further supported by some genetic evidences showing a correlation between serum leptin levels, leptin receptor polymorphisms, and the risk of breast cancer [10,11]. In sum, although further prospective data are needed, leptin should be mentioned among the key factors in understanding the relationship between hyperinsulinemia and related metabolic factors in subjects with cancer risk.…”

supporting

confidence: 53%

Link between insulin and metabolic disorders in cancer: does leptin play a key role?

Malandrino¹,

Leggio²,

Addolorato³

et al. 2008

Breast Cancer Res Treat

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“…However, the molecular mechanisms of how leptin signaling regulates VEGFR-2 are largely unknown (Beecken et al 2000;Cirillo et al 2008;Hausman and Richardson 2004). In addition, leptin induces transactivation of the HER2/neu proto-oncogene (c-erbB-2), and interacts with insulin like growth factor-1 to transactivate the EGF-receptor (EGFR) (Fiorio et al 2008;Soma et al 2008). Leptin stimulates aromatase expression and activation of ER (Catalano et al 2003;Cirillo et al 2008).…”

Section: Leptin Regulation Of Vegfr-2mentioning

confidence: 99%