glucagon-like-peptide-1 and Breast-Neoplasms

Diabetes Mellitus (DM) has been one of the well known risk factors of breast cancer (BC) development and also associated with adverse clinical outcomes of BC patients. Glucagon-like peptide-1 (GLP-1) receptor agonists have been used as antidiabetic therapeutic agents and recent epidemiological studies have reported their use to be correlated with increased BC risks. However, biological or pathological details have remained unknown. Therefore, in this study, we examined the status of GLP-1 receptor (GLP-1R) in BC with and without DM and correlated the findings with the clinicopathological factors of the patients to explore the possible involvement of GLP-1 in BC pathology.. We immunolocalized GLP-1R in cancer and adjacent non-pathological breast tissues in BC patients with DM (125 cases) and without DM (58 cases). We then compared the status of GLP-1R with that of fibroblast growth factor 7 (FGF7) and fibroblast growth factor receptor 2 (FGFR2), Ki-67 labeling index (Ki-67 LI) and disease free survival (DFS) of the patients and also between cancerous and non-pathological breast tissues.. GLP-1R immunoreactivity was significantly higher (p = 0.044) in the patients with DM than without in carcinoma tissues. However, this was detected only in invasive carcinoma (p < 0.01) and not in non-invasive carcinoma nor non-pathological mammary glands. FGF7 was significantly correlated with the status of GLP-1R in BC (p = 0.045). In addition, in ER positive BC cases, those with GLP-1R positive status tended to have higher Ki-67 LI of more than 14% (p = 0.070).. These findings all demonstrated the possible association between GLP-1R status and biological features of BC, especially of invasive BC in DM patients.

Topics: Breast Neoplasms; Diabetes Mellitus; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents

 To determine whether the use of glucagon-like peptide-1 (GLP-1) analogues, compared with the use of dipeptidylpeptidase-4 (DPP-4) inhibitors, is associated with an increased risk of incident breast cancer in patients with type 2 diabetes..  Population based cohort study..  Clinical Practice Research Datalink, UK..  44 984 women aged at least 40 years, who were newly treated with glucose lowering drugs between 1 January 2007 and 31 March 2015, with follow-up until 31 March 2016..  Time varying use of GLP-1 analogues compared with use of DPP-4 inhibitors, with exposures lagged by one year for latency purposes. Time dependent Cox proportional hazards models were used to estimate adjusted hazard ratios with 95% confidence intervals of incident breast cancer associated with use of GLP-1 analogues overall, by cumulative duration of use, and time since initiation..  The cohort was followed for a mean of 3.5 years (standard deviation 2.2), with 549 incident events of breast cancer recorded (crude incidence 3.5 (95% confidence interval 3.3 to 3.8) per 1000 person years). Overall, compared with use of DPP-4 inhibitors, use of GLP-1 analogues was not associated with an increased risk of breast cancer (incidence 4.4 v 3.4 per 1000 person years; hazard ratio 1.40 (95% confidence interval 0.91 to 2.16)). Hazard ratios gradually increased with longer durations of use, with a peak between two to three years of GLP-1 use (2.66 (95% confidence interval 1.32 to 5.38)), and returned closer to the null after more than three years of use (0.98 (0.24 to 4.03)). A similar pattern was observed with time since initiation of GLP-1 analogues..  In this population based cohort study, use of GLP-1 analogues was not associated with an overall increased risk of breast cancer. Although it is not possible to rule out a tumour promoter effect, the observed duration-response associations are likely the result of a transient increase in detection of breast cancers in GLP-1 analogue users.

Topics: Aged; Breast Neoplasms; Cohort Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Middle Aged; Risk Factors; Time Factors; United Kingdom

The incretin hormone glucagon-like peptide (GLP)-1 is secreted from intestinal L cells in response to food intake, and promotes insulin secretion and pancreatic β-cell proliferation. Reduced GLP-1 levels are observed in obesity and type 2 diabetes mellitus (T2DM) and are associated with reduced insulin secretion and increased insulin resistance. GLP-1 mediates its activities through activation of a G-protein coupled receptor, which is expressed in the pancreas, as well as other tissues. Long-acting GLP-1 receptor (GLP-1R) agonists, such as exendin-4, are currently approved for the treatment of T2DM. As obesity and T2DM are associated with increased risk of breast cancer, we aimed to explore the effects of GLP-1 and exendin-4, on breast cancer cells. Treatment with GLP-1 or exendin-4 reduced viability and enhanced apoptosis of breast cancer cells but did not affect viability of nontumorigenic cells. Moreover, exendin-4 attenuated tumor formation by breast cancer cells in athymic mice. Treatment with either GLP-1 or exendin-4 elevated cAMP levels, activated the down-stream target CREB, and enhanced CRE promoter transcription, in breast cancer cells. Moreover, inhibition of exendin-4-induced adenylate cyclase activation restored cell viability, thus suggesting cAMP as a principle mediator of exendin-4 anti-tumorigenic activity. While the pancreatic form of the GLP-1R could not be detected in breast cancer cells, several lines of evidence indicated the existence of an alternative GLP-1R in mammary cells. Thus, internalization of GLP-1 into MCF-7 cells was evidenced, infection of MCF-7 cells with the pancreatic receptor enhanced proliferation, and treatment with exendin-(9-39), a GLP-1R antagonist, further increased cAMP levels. Our studies indicate the incretin hormone GLP-1 as a potent inducer of cAMP and an inhibitor of breast cancer cell proliferation. Reduced GLP-1 levels may, therefore, serve as a novel link between obesity, diabetes mellitus, and breast cancer.

Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Activators; Enzyme Inhibitors; Exenatide; Female; Gene Expression Regulation, Neoplastic; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Mice; Mice, Nude; p38 Mitogen-Activated Protein Kinases; Peptides; Receptors, Glucagon; Response Elements; Signal Transduction; Time Factors; Transcriptional Activation; Transfection; Up-Regulation; Venoms; Xenograft Model Antitumor Assays

Topics: Animals; Breast Neoplasms; Calcitonin; Carcinoma, Medullary; Clinical Trials as Topic; Comorbidity; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Disease Susceptibility; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Infections; Liraglutide; Pancreatitis; Pharmacovigilance; Pioglitazone; Pyrazines; Risk Assessment; Safety-Based Drug Withdrawals; Sitagliptin Phosphate; Species Specificity; Thiazolidinediones; Thyroid Neoplasms; Triazoles; Urinary Bladder Neoplasms

Weight gain in women receiving chemotherapy for breast cancer is associated with a higher risk of recurrence but its mechanisms are poorly understood.. To investigate this, we assessed the metabolic, cytokine, and appetite-related peptide alterations during adjuvant chemotherapy for early breast cancer in postmenopausal women, and correlated these with body mass measurements. Specifically, we performed global metabolic profiling using (1)H-nuclear magnetic resonance spectroscopy of sequential sera, examined ghrelin immunoreactivity, RIAs for GLP-1 and peptide YY, and electrochemiluminescent cytokine analyses (tumor necrosis factor-alpha and interleukin-6) on sequential samples.. In those who gained >1.5 kg, several metabolite levels were positively associated with weight gain, specifically lactate, which was 63.5% greater in patients with increased body weight during chemotherapy compared with those with no weight gain (P < 0.01; the prespecified primary end point). A strong correlation (r = 0.7, P < 0.001) was detected between the rate of weight change and serum lactate levels, and on average, lactate levels exhibited the greatest metabolic response to chemotherapy, increasing by up to 75%. Normalized levels of peptide YY were also observed to be elevated in patients not gaining weight posttreatment (+30% compared with -7% for the weight gain group; P < 10(-4)). Baseline lactate, alanine, and body fat were all prognostic for weight gain (area under the receiver operator characteristic curves, >0.77; P < 0.05). No associations were observed between any other parameter and weight gain, including cytokine levels.. Metabonomics identifies excess energy expenditure pathways perturbed during chemotherapy for breast cancer, and establishes a significant association between serum lactate, body fat, and substantive weight gain during chemotherapy.

Topics: Biomarkers; Body Mass Index; Breast Neoplasms; Female; Glucagon-Like Peptide 1; Humans; Interleukin-6; Lactates; Peptide YY; Postmenopause; Tumor Necrosis Factor-alpha; Weight Gain