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Metformin and breast cancer

Maike Zimmermann, Aruni P S Arachchige-Don, Michaela S Donaldson, Tommaso Patriarchi, Mary C Horne
Definition of cell cycle control proteins that modify tumor cell resistance to estrogen (E2) signaling antagonists could inform clinical choice for estrogen receptor positive (ER+) breast cancer (BC) therapy. Cyclin G2 (CycG2) is upregulated during cell cycle arrest responses to cellular stresses and growth inhibitory signals and its gene, CCNG2, is directly repressed by E2-bound ER complexes. Our previous studies showed that blockade of HER2, PI3K and mTOR signaling upregulates CycG2 expression in HER2+ BC cells, and that CycG2 overexpression induces cell cycle arrest...
October 18, 2016: Cell Cycle
Mohamed Alalem, Alpana Ray, Bimal K Ray
Activation of mTOR is implicated in the development and progression of breast cancer. mTOR inhibition exhibited promising antitumor effects in breast cancer; however, its effect is compromised by several feedback mechanisms. One of such mechanisms is the upregulation of mTOR pathway in breast cancer cells. Despite the established role of mTOR activation in breast cancer, the status of total mTOR protein and its impact on the tumor behavior and response to treatment are poorly understood. Besides, the mechanisms underlying mTOR protein degradation in normal and cancer breast cells are still largely unknown...
October 17, 2016: Cancer Medicine
Mariusz Dąbrowski, Elektra Szymańska-Garbacz, Zofia Miszczyszyn, Tadeusz Dereziński, Leszek Czupryniak
BACKGROUND: The risk of several types of cancer is increased in type 2 diabetes mellitus. The earliest possible diagnosis of cancer - difficult within regular outpatient diabetes care - is of utmost importance for patients' survival. The aim of this multicenter, retrospective (years 1998-2015), case-control study was to identify risk factors associated with malignancy in subjects with diabetes treated in a typical outpatient setting. METHODS: In the databases of 3 diabetic and 1 primary care clinics 203 patients (115 women) with type 2 diabetes mellitus who developed malignancy while treated for diabetes were identified...
October 10, 2016: BMC Cancer
Ryan Kolb, Liem Phan, Nicholas Borcherding, Yinghong Liu, Fang Yuan, Ann M Janowski, Qing Xie, Kathleen R Markan, Wei Li, Matthew J Potthoff, Enrique Fuentes-Mattei, Lesley G Ellies, C Michael Knudson, Mong-Hong Lee, Sai-Ching J Yeung, Suzanne L Cassel, Fayyaz S Sutterwala, Weizhou Zhang
Obesity is associated with an increased risk of developing breast cancer and is also associated with worse clinical prognosis. The mechanistic link between obesity and breast cancer progression remains unclear, and there has been no development of specific treatments to improve the outcome of obese cancer patients. Here we show that obesity-associated NLRC4 inflammasome activation/ interleukin (IL)-1 signalling promotes breast cancer progression. The tumour microenvironment in the context of obesity induces an increase in tumour-infiltrating myeloid cells with an activated NLRC4 inflammasome that in turn activates IL-1β, which drives disease progression through adipocyte-mediated vascular endothelial growth factor A (VEGFA) expression and angiogenesis...
October 6, 2016: Nature Communications
C Coyle, F H Cafferty, C Vale, R E Langley
BACKGROUND: Metformin use has been associated with a reduced risk of developing cancer and an improvement in overall cancer survival rates in meta-analyses, but, to date, evidence to support the use of metformin as an adjuvant therapy in individual cancer types has not been presented. PATIENTS AND METHODS: We systematically searched research databases, conference abstracts and trial registries for any studies reporting cancer outcomes for individual tumour types in metformin users compared with non-users, and extracted data on patients with early-stage cancer...
September 28, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Hadar Goldvaser, Shulamith Rizel, Daniel Hendler, Victoria Neiman, Daniel Shepshelovich, Tzippy Shochat, Aaron Sulkes, Baruch Brenner, Rinat Yerushalmi
Purpose. To evaluate the associations between metformin, insulin, statins, and levothyroxine and breast cancer characteristics and outcome. Methods. Retrospective chart review of patients treated in our institute for early estrogen receptor (ER) positive, human epidermal growth factor receptor 2 negative breast cancer, whose tumors were sent to Oncotype DX (ODX) analysis. Patients were grouped according to medications usage during the time of breast cancer diagnosis. Each group was compared to the rest of the study population...
2016: International Journal of Endocrinology
Nifang Niu, Tongzheng Liu, Junmei Cairns, Reynold C Ly, Xianglin Tan, Min Deng, Brooke L Fridley, Krishna R Kalari, Ryan P Abo, Gregory Jenkins, Anthony Batzler, Erin E Carlson, Poulami Barman, Sebastian Moran, Holger Heyn, Manel Esteller, Liewei Wang
Metformin is currently considered as a promising anticancer agent in addition to its anti-diabetic effect. To better individualize metformin therapy and explore novel molecular mechanisms in cancer treatment, we conducted a pharmacogenomic study using 266 lymphoblastoid cell lines (LCLs). Metformin cytotoxicity assay was performed using the MTS assay. Genome-wide association (GWA) analyses were performed in LCLs using 1.3 million SNPs, 485k DNA methylation probes, 54k mRNA expression probe sets, and metformin cytotoxicity (IC50s)...
September 11, 2016: Human Molecular Genetics
Sung-Eun Hong, Chang Soon Kim, Sungkwan An, Hyun-Ah Kim, Sang-Gu Hwang, Jie-Young Song, Jin Kyung Lee, Jungil Hong, Jong-Il Kim, Woo Chul Noh, Hyeon-Ok Jin, In-Chul Park
Previous studies have shown that hypoxia can reverse DCA/metformin-induced cell death in breast cancer cells. Therefore, targeting hypoxia is necessary for therapies targeting cancer metabolism. In the present study, we found that TRAIL can overcome the effect of hypoxia on the cell death induced by treatment of DCA and metformin in breast cancer cells. Unexpectedly, DR5 is upregulated in the cells treated with DCA/metformin, and sustained under hypoxia. Blocking DR5 by siRNA inhibited DCA/metformin/TRAIL-induced cell death, indicating that DR5 upregulation plays an important role in sensitizing cancer cells to TRAIL-induced cell death...
September 23, 2016: Biochemical and Biophysical Research Communications
Paula Cabello, Begoña Pineda, Eduardo Tormo, Ana Lluch, Pilar Eroles
Metformin, a drug approved for diabetes type II treatment, has been associated with a reduction in the incidence of breast cancer and metastasis and increased survival in diabetic breast cancer patients. High levels of miR-26a expression have been proposed as one of the possible mechanisms for this effect; likewise, this miRNA has also been associated with survival/apoptosis processes in breast cancer. Our aim was to evaluate if miR-26a and some of its targets could mediate the effect of metformin in breast cancer...
2016: International Journal of Molecular Sciences
Jessica A Martinez, Pavani Chalasani, Cynthia A Thomson, Denise Roe, Maria Altbach, Jean-Philippe Galons, Alison Stopeck, Patricia A Thompson, Diana Evelyn Villa-Guillen, H-H Sherry Chow
BACKGROUND: Two-thirds of U.S. adult women are overweight or obese. High body mass index (BMI) and adult weight gain are risk factors for a number of chronic diseases, including postmenopausal breast cancer. The higher postmenopausal breast cancer risk in women with elevated BMI is likely to be attributable to related metabolic disturbances including altered circulating sex steroid hormones and adipokines, elevated pro-inflammatory cytokines, and insulin resistance. Metformin is a widely used antidiabetic drug that has demonstrated favorable effects on metabolic disturbances and as such may lead to lower breast cancer risk in obese women...
2016: BMC Cancer
O P Shatova, Eu V Butenko, Eu V Khomutov, D S Kaplun, I Eu Sedakov, I I Zinkovych
Large-scale epidemiological and clinical studies have demonstrated the efficacy of metformin in oncology practice. However, the mechanisms of implementation of the anti-tumor effect of this drug there is still need understanding. In this study we have investigated the effect of metformin on the activity of adenosine deaminase and respectively adenosinergic immunosuppression in tumors and their microenvironment. The material of the study was taken during surgery of breast cacer patients receiveing metformin, and also patients which did not take this drug...
March 2016: Biomedit︠s︡inskai︠a︡ Khimii︠a︡
Jin Hou, Fen Li, Xinhua Li, Qibing Mei, Man Mi
Objective To investigate the effect of metformin, alone or in combination with Lily polysaccharide 1 (LP1), on cell viability and apoptosis in MCF-7 human breast cancer cells. Methods LP1 (0.5, 1.0 mg/mL) and metformin (5, 10, 20, 50 mmol/L) were added into MCF-7 cell culture medium, followed by incubating for 72 hours in carbon dioxide incubators at 37DegreesCelsius. MCF-7 cell proliferation was determined using MTT assay; the apoptosis and cell cycle of MCF-7 cells were examined using annexin V-FITC/PI double staining combined with flow cytometry; Western blotting was used to determine the content of Bcl-2, Bax, adenosine monophosphate-activated protein kinase (AMPK) and phosphorated AMPK (p-AMPK) proteins...
June 2016: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
Jie Li, Kecheng Lei, Zengrui Wu, Weihua Li, Guixia Liu, Jianwen Liu, Feixiong Cheng, Yun Tang
As the recent development of high-throughput technologies in cancer pharmacogenomics, there is an urgent need to develop new computational approaches for comprehensive identification of new pharmacogenomic biomarkers, such as microRNAs (miRNAs). In this study, a network-based framework, namely the SMiR-NBI model, was developed to prioritize miRNAs as potential biomarkers characterizing treatment responses of anticancer drugs on the basis of a heterogeneous network connecting drugs, miRNAs and genes. A high area under the receiver operating characteristic curve of 0...
June 14, 2016: Oncotarget
K Kalinsky, T Zheng, H Hibshoosh, X Du, P Mundi, J Yang, S Refice, S M Feldman, B Taback, E Connolly, K D Crew, M A Maurer, D L Hershman
PURPOSE: Reverse Phase Protein Array (RPPA) is a high-throughput antibody-based technique to assess cellular protein activity. The goal of this study was to assess protein marker changes by RPPA in tumor tissue from a pre-surgical metformin trial in women with operable breast cancer (BC). METHODS: In an open-label trial, metformin 1500-mg PO daily was administered prior to resection in 35 non-diabetic patients with stage 0-III BC, body mass index ≥25 kg/m(2)...
June 15, 2016: Clinical & Translational Oncology
Takao Yamazaki, Amit Desai, Ronald Goldwater, David Han, Kenneth C Lasseter, Corrie Howieson, Shahzad Akhtar, Donna Kowalski, Christopher Lademacher, Diane Rammelsberg, Robert Townsend
This article summarizes 4 phase 1 trials that explored interactions between the novel, triazole antifungal isavuconazole and substrates of the drug transporters breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein-1 (MATE1), organic anion transporters 1/3 (OAT1/OAT3), organic anion-transporting polypeptide 1B1 (OATP1B1), organic cation transporters 1/2 (OCT1/OCT2), and P-glycoprotein (P-gp). Healthy subjects received single doses of atorvastatin (20 mg; OATP1B1 and P-gp substrate), digoxin (0...
June 8, 2016: Clinical Pharmacology in Drug Development
Kyung-Min Lee, Minju Lee, Jiwoo Lee, Sung Wuk Kim, Hyeong-Gon Moon, Dong-Young Noh, Wonshik Han
Metformin, which is a drug commonly used to treat type 2 diabetes, has shown anti-tumor effects in numerous experimental, epidemiologic, observational, and clinical studies. Here, we report a new metformin derivative, metformin-butyrate (MFB). Compared to metformin-HCl, it more potently activates AMPK, inhibits mTOR, and impairs cell cycle progression at S and G2/M phases. Moreover, MFB inhibits the mammosphere formation of breast cancer cells and shows cytotoxic effects against CD44+CD24-/low populations in vitro and in vivo, indicating that it might have preferential effects on the cancer stem cell population...
May 20, 2016: Oncotarget
Adriana Albini, Andrea DeCensi, Franco Cavalli, Alberto Costa
At several recent, internationally attended scientific meetings, including the American Association for Cancer Research (AACR)'s "Shaping the Future of Cancer Prevention: A Roadmap for Integrative Cancer Science and Public Health" summit in Leesburg (VA) and the AACR Annual Meeting in New Orleans, the focus on cancer prevention to reduce cancer-related deaths was extensively discussed with renewed attention and emphasis. Cancer prevention should be actively proposed even to healthy individuals, and not just to individuals with high cancer risk...
September 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
J Wojciechowska, W Krajewski, M Bolanowski, T Kręcicki, T Zatoński
Diabetes mellitus (DM), one of the most common life-threatening illnesses worldwide, is a group of metabolic diseases, characterized by sustained hyperglycemia. The global prevalence of diabetes mellitus among adults reached 387 millions in 2014 and is still rising. It is suggested there is a strong association between diabetes mellitus (especially type 2 diabetes mellitus) and carcinogenesis. The possible biological links between diabetes mellitus and cancer comprise hyperinsulinemia, hyperglycemia and fat-induced chronic inflammation...
May 2016: Experimental and Clinical Endocrinology & Diabetes
Zhen-Yuan Gao, Zhe Liu, Ming-Hong Bi, Jing-Jing Zhang, Zheng-Quan Han, Xiao Han, Hong-Ya Wang, Guo-Ping Sun, Hao Liu
Breast cancer is the most commonly occurring cancer and second leading cause of mortality in women. Metformin is a widely prescribed anti-hyperglycemic drug, which is emerging as a potential cancer preventative and treatment agent. However, the mechanisms underlying the suppressive effects of metformin on cancer cell growth and the induction of cancer cell apoptosis are not fully elucidated. The present study aimed to identify the pathways regulated by metformin in two breast cancer cell lines, MDA-MB-231 and MDA-MB-435...
May 2016: Experimental and Therapeutic Medicine
Maruša Rajh, Klemen Dolinar, Katarina Miš, Mojca Pavlin, Sergej Pirkmajer
Epidemiological studies indicate that metformin, a widely used type 2 diabetes drug, might reduce breast cancer risk and mortality in patients with type 2 diabetes. Metformin might protect against breast cancer indirectly by ameliorating systemic glucose homeostasis. Alternatively, it might target breast cancer cells directly. However, experiments using MDA-MB-231 cells, a standard in vitro breast cancer model, produced inconsistent results regarding effectiveness of metformin as a direct anti-cancer agent...
2016: PloS One
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