Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer

Vona-Davis, Linda; Howard-McNatt, Marissa; Rose, David P.

doi:10.1111/j.1467-789x.2007.00396.x

Cited by 241 publications

(199 citation statements)

References 142 publications

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“…The highest doses of leptin (500 ng/mL) induced rapid downregulation of HER2, most likely due to ligand-dependent internalization [3]. Similar induction of Tyr1248-HER2 was observed with EGF, a known activator of this receptor [4] (Fig. 2, Fiorio et al).…”

Section: Bodysupporting

confidence: 54%

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: Bodysupporting

confidence: 54%

HER2/Leptin Crosstalk in Breast Cancer

Surmacz¹

2009

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“…Indeed, serum total estradiol levels have been shown to be related to BMI, with an inverse U-shape before 17,18 and a linear increase after menopause. 12 Furthermore, the possible relationship between central obesity and breast cancer risk is consistent with a role of insulin resistance in pre-and postmenopausal women, 12,13,19,20 as central obesity is a predictor of insulin resistance independently of general obesity. 13 To clarify potential associations between various anthropometric measures and breast cancer risk according to menopausal status and to the hormone receptor status of the cancer, we used data from the large French prospective E3N cohort that provided detailed information on HC, WC, WHR, height, weight and BMI.…”

Section: Introductionmentioning

confidence: 64%

Hip circumference is associated with the risk of premenopausal ER−/PR− breast cancer

et al. 2011

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Objective: We evaluated the relationship between hip and waist circumferences (HCs, WCs), waist-to-hip ratio, height, weight and body mass index (BMI) and breast cancer risk according to menopausal status of women and cancer hormone receptor status. Design: We used data from the French E3N longitudinal prospective cohort. Subjects: In the total population of 63 726 women who were analyzed, 1887 breast cancer cases were diagnosed during follow-up. Results: Among postmenopausal women, the risk of ER þ /PR þ breast cancer increased with increasing weight, BMI, and both HCs and WCs, although these two associations disappeared after adjustment for BMI. No association was seen with ERÀ/PRÀ breast cancers. Among premenopausal women, among the different factors studied, HC only (no association was observed for any of the different factors studied except for HC) was associated with an increased risk of ER þ /PR þ breast cancer after adjustment for BMI (hazard ratio (HR) ¼ 1.65; (1.04-2.62) when comparing the highest to lowest tertile; P-trend across tertiles ¼ 0.03) and of ERÀ/PRÀ breast cancer both before and after adjustment for BMI (HR ¼ 2.85 (1.33-6.13); P-trend o0.01, and HR ¼ 3.13 (1.19-8.27) P-trend ¼ 0.02, respectively). In the latter group, the association with HC was observed whatever the WC (HR ¼ 2.81 (1.18-6.70) and HR ¼ 2.79 (1.16-6.76) in women with high HC/low WC and high HC/high WC, respectively). Conclusion: The increase in risk of premenopausal breast cancer associated with large HC for both ER þ /PR þ and ERÀ/PRÀ subtypes may provide insight into a specific risk factor for premenopausal breast cancer.

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“…To account for the notions that type 2 diabetes and metabolic syndrome (MS) have been associated with increased serum leptin levels and elevated risk of breast cancer (Vona-Davis et al, 2007), individuals with a history of type 2 diabetes and/or MS were excluded from this study. On the basis of the hospital chart number, the cases involved 297 women consecutively selected from subjects with a first confirmed histopathologic diagnosis of breast carcinoma in the age range of 24 -72 years.…”

Section: Case and Control Selectionmentioning

confidence: 99%

Circulating levels of leptin, adiposity and breast cancer risk

et al. 2009

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The present case -control study was to investigate the relationships of plasma leptin level and anthropometric measures of adiposity with the risk of breast cancer. Questionnaire information, anthropometric measures and blood samples were taken before treatment from 297 incident cases with breast cancer and 593 controls admitted for health examination at the Tri-Service General Hospital, Taipei, between 2004 and. Plasma levels of leptin were measured by RIA. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for assessing the associations. Overall, higher leptin concentrations were significantly associated with an increased risk of breast cancer (OR (95% CI) for top vs bottom tertile of leptin was 1.63 (1.07 -2.49), P trend ¼ 0.009). Waist circumference was a significant anthropometric factor for breast cancer in both pre-and postmenopausal women. Furthermore, the associations of leptin with breast cancer risk remained after adjustment for obesity indices. These results suggest that leptin may have an independent role in breast tumorigenesis. Regardless of the impact of circulating leptin, more research is needed to elucidate molecular mechanisms and local leptin levels that are critical for the development of breast cancers. British Journal of Cancer (2009) Epidemiologic evidence suggested that obesity is associated with an increased risk of breast cancer in women, primarily in postmenopausal population (Calle and Thun, 2004). However, the molecular mechanisms underlying the obesity -breast cancer link are not fully clear. One important factor contributing to obesity -breast carcinogenesis might be an excess exposure of mammary epithelium to various bioactive substances produced by the adipose tissue (adipokines). Indeed, adipose tissue is a source of oestrogens, insulin and insulin-like growth factors, all of which are believed to be involved in mammary tumorigenesis (Schäffler et al, 2007). The most prominent adipokine is leptin, which is best known as a regulator of food intake and energy balance in the hypothalamus (Auwerx and Staels, 1998). Interestingly, leptin is also implicated in the regulation of reproductive hormones and function . Notably, leptin consistently stimulates the proliferation of benign and malignant epithelial breast cells in vitro as measured by DNA synthesis and upregulation of downstream regulators of cellular proliferation (Dieudonne et al, 2002;Hu et al, 2002). Thus, the intriguing possibility exists that leptin could be directly related to breast carcinogenesis by underlying the effects of obesity on cancer development. We have undertaken a case -control study to test this hypothesis. MATERIALS AND METHODS Case and control selectionThis case -control study was conducted at the Tri-Service General Hospital, Taipei, Taiwan, from January 2004 to November 2006. To account for the notions that type 2 diabetes and metabolic syndrome (MS) have been associated with increased serum leptin levels and elevated risk of breast cancer (Vona-D...

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Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer

Cited by 241 publications

References 142 publications

HER2/Leptin Crosstalk in Breast Cancer

HER2/Leptin Crosstalk in Breast Cancer

Hip circumference is associated with the risk of premenopausal ER−/PR− breast cancer

Circulating levels of leptin, adiposity and breast cancer risk

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