Obesity: an endocrine tumor?

Dizdar, Ömer; Alyamaç, Evrim

doi:10.1016/j.mehy.2004.01.046

Cited by 46 publications

(27 citation statements)

References 11 publications

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“…It is possible to hypothesise that calcium levels in postmenopausal and obese women may reflect PTH levels rather than vitamin-D levels and that calcium levels in premenopausal women may mainly be a marker of vitamin-D levels. Obese are known to have an altered endocrine metabolism [44] and possibly factors as insulin or insulin-like growth factor (IGF) could be related to our observations [45].…”

Section: Discussionmentioning

confidence: 91%

Serum calcium and breast cancer risk: results from a prospective cohort study of 7,847 women

Almquist

Manjer

Bondeson

et al. 2007

Cancer Causes Control

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Experimental and epidemiological studies suggest that calcium-regulating hormonesparathyroid hormone (PTH) and vitamin D -may be associated with breast cancer risk.No prospective cohort study has investigated the association between pre-diagnostic calcium levels and subsequent risk of breast cancer. We have examined this in a cohort of 7847 women where serum calcium levels and established risk factors for breast cancer had been assessed at baseline. During a mean follow-up of 17.8 years, 437 incident breast cancer cases were diagnosed. Incidence of breast cancer was calculated in different quartiles of serum calcium levels and a Cox's proportional hazards analysis was used to obtain corresponding relative risks (RR), with a 95% confidence interval (CI), adjusted for potential confounders.In premenopausal women, serum calcium levels were inversely associated with breast cancer risk in a dose-response manner. The adjusted RR (95% CI) of breast cancer was in the 2 nd calcium quartile 0.91 (0.65-1.30), in the 3 rd quartile 0.89 (0.60-1.31), and in the 4 th quartile 0. 56 (0.32-0.98), as compared to the 1 st calcium quartile. In postmenopausal overweight women (BMI>25), breast cancer risk was higher in calcium quartiles 2 to 4 as compared to the 1 st quartile. Our findings may have implications for primary prevention of breast cancer and for the management of asymptomatic primary hyperparathyroidism.

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Section: Discussionmentioning

confidence: 91%

Serum calcium and breast cancer risk: results from a prospective cohort study of 7,847 women

Almquist

Manjer

Bondeson

et al. 2007

Cancer Causes Control

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“…Obesity is considered as an endocrine disorder mediating its biological effects via adipocytokines secreted primarily from white adipose tissue (3)(4)(5). Studies have shown that adipose tissue can directly influence tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Leptin-induced Growth Stimulation of Breast Cancer Cells Involves Recruitment of Histone Acetyltransferases and Mediator Complex to CYCLIN D1 Promoter via Activation of Stat3

Saxena

Vertino

Anania

et al. 2007

Journal of Biological Chemistry

185

158

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Numerous epidemiological studies documented that obesity is a risk factor for breast cancer development in postmenopausal women. Leptin, the key player in the regulation of energy balance and body weight control also acts as a growth factor on certain organs in both normal and disease state. In this study, we analyzed the role of leptin and the molecular mechanism(s) underlying its action in breast cancer cells that express both short and long isoforms of leptin receptor. Leptin increased MCF7 cell population in the S-phase of the cell cycle along with a robust increase in CYCLIN D1 expression. Also, leptin induced Stat3-phosphorylation-dependent proliferation of MCF7 cells as blocking Stat3 phosphorylation with a specific inhibitor, AG490, abolished leptin-induced proliferation. Using deletion constructs of CYCLIN D1 promoter and chromatin immunoprecipitation assay, we show that leptin induced increase in CYCLIN D1 promoter activity is mediated through binding of activated Stat3 at the Stat binding sites and changes in histone acetylation and methylation. We also show specific involvement of coactivator molecules, histone acetyltransferase SRC1, and mediator complex in leptin-mediated regulation of CYCLIN D1 promoter. Importantly, silencing of SRC1 and Med1 abolished the leptin induced increase in CYCLIN D1 expression and MCF7 cell proliferation. Intriguingly, recruitment of both SRC1 and Med1 was dependent on phosphorylated Stat3 as AG490 treatment inhibited leptin-induced recruitment of these coactivators to CYCLIN D1 promoter. Our data suggest that CYCLIN D1 may be a target gene for leptin mediated growth stimulation of breast cancer cells and molecular mechanisms involve activated Stat3-mediated recruitment of distinct coactivator complexes.

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“…One places adipocytes and their autocrine, paracrine, and endocrine functions at center stage. This hypothesis proposes that obesity should be considered as an endocrine tumor (45) and adipocyte as an endocrine cell (46). In such a hypothesis the following pathways can be included in obesity conditioned breast cancer among women: a) increased local estrogen biosynthesis in breast via aromatase activity increasing with age and BMI (47) and modulated by tumor necrosis factor α or interleukin 6 (48); b) insulin resistance and increased insulin concentrations (49) together with overexpression of IGF-I (50); c) decreased concentrations of sex-hormone-binding globulin (SHBG) due to hyperinsulinemia that leads to an increase in the bioavaliable fraction of circulating estradiol (16,51); d) adipokines secreted by adipocytes (52); e) leptin resistance in which the membrane leptin receptor and the JAK-STAT pathway are blocked with results of increased intracellular concentrations of lipid metabolites, increased non-oxidative metabolism by adipocytes, and stimulation of the cell estrogen cycle [under these conditions the oncogenic property is activated via the shared mitogen-activated protein kinase (MAPK), mitogen/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK) cellular pathways (17,53)]; and f) a novel complement-related hormone secreted exclusively by adipocytes, adiponectin (16).…”

Section: ) -------------------------------------------------mentioning

confidence: 99%

A polymorphism C3435T of the MDR-1 gene associated with smoking or high body mass index increases the risk of sporadic breast cancer in women

Žúbor

Lasabová²,

Hatok³

et al. 2007

Oncol Rep

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Abstract. The human multidrug resistance gene 1 (MDR-1) encodes a plasma membrane P-glycoprotein (P-gp) that functions as the transmembrane efflux pump for various structurally unrelated anticancer agents and toxins. Polymorphisms in the MDR-1 gene may have an impact on the expression and function of P-gp, thereby influencing the susceptibility to various diseases, including cancer. We investigated the incidence of C3435T polymorphisms at exon 26 in the MDR-1 gene in 92 women with breast cancer and potential association of altered genotypes with smoking and high body mass index in cancer development among patients. The MDR-1 C3435T allelotype and genotype analysis revealed a high incidence (75.0%) of polymorph alteration in the MDR-1 gene. The frequencies of homozygous T/T, heterozygous C/T and homozygous C/C genotypes were 25.0, 50.0 and 25.0%, respectively. The risk of breast carcinoma in patients with MDR-1 polymorphism was significantly associated with the higher body mass index, where women with BMI >30 kg/m 2 and C allele in genotype had a higher risk of disease compared to patients with lower amounts of body fat tissue (p=0.0439). The risk was highest for the homozygous carriers of C allele with BMI >30 kg/m 2 compared to patients with BMI 25.1-30 or ≤25 kg/m 2 (OR 3.65, 95% CI 0.94-14.20; or OR 2.50, 95% CI 0.55-11.41), respectively. Consistent with the results of genotyping and BMI analyses, smoking patients harboring the C/T or C/C genotype had an increased risk of cancer (OR 1.28, OR 1.58,, respectively) when exposed to carcinogens in tobacco smoke, although it was not statistically significant. Our findings suggest that the MDR-1 C3435T polymorphism occurs in high incidence among women with breast carcinoma where C allele carriers have increased risk of developing cancer when exposed to toxic substances. Our observations are the first that indicate this polymorphism as a modulator of health to be associated with an increased risk of breast cancer.

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Obesity: an endocrine tumor?

Cited by 46 publications

References 11 publications

Serum calcium and breast cancer risk: results from a prospective cohort study of 7,847 women

Serum calcium and breast cancer risk: results from a prospective cohort study of 7,847 women

Leptin-induced Growth Stimulation of Breast Cancer Cells Involves Recruitment of Histone Acetyltransferases and Mediator Complex to CYCLIN D1 Promoter via Activation of Stat3

A polymorphism C3435T of the MDR-1 gene associated with smoking or high body mass index increases the risk of sporadic breast cancer in women

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