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Metformin and triple negative breast cancer

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https://www.readbyqxmd.com/read/28423712/model-based-unsupervised-learning-informs-metformin-induced-cell-migration-inhibition-through-an-ampk-independent-mechanism-in-breast-cancer
#1
Arjun P Athreya, Krishna R Kalari, Junmei Cairns, Alan J Gaglio, Quin F Wills, Nifang Niu, Richard Weinshilboum, Ravishankar K Iyer, Liewei Wang
We demonstrate that model-based unsupervised learning can uniquely discriminate single-cell subpopulations by their gene expression distributions, which in turn allow us to identify specific genes for focused functional studies. This method was applied to MDA-MB-231 breast cancer cells treated with the antidiabetic drug metformin, which is being repurposed for treatment of triple-negative breast cancer. Unsupervised learning identified a cluster of metformin-treated cells characterized by a significant suppression of 230 genes (p-value < 2E-16)...
March 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28350075/co-treatment-of-breast-cancer-cells-with-pharmacologic-doses-of-2-deoxy-d-glucose-and-metformin-starving-tumors
#2
Ulrike Wokoun, Martin Hellriegel, Günter Emons, Carsten Gründker
A characteristic of tumor cells is the increased aerobic glycolysis for energy production. Thus, inhibition of glycolysis represents a selective therapeutic option. It has been shown that glycolysis inhibitor 2-deoxy-D-glucose (2DG) induces apoptotic cell death in different tumor entities. In addition, the antitumor activity of the anti-diabetic drug metformin has been demonstrated. In the present study, we aimed to ascertain whether the combination of pharmacologic doses of 2DG with metformin increases the antitumor efficacy...
April 2017: Oncology Reports
https://www.readbyqxmd.com/read/28324269/metformin-sensitizes-triple-negative-breast-cancer-to-proapoptotic-trail-receptor-agonists-by-suppressing-xiap-expression
#3
Elena Strekalova, Dmitry Malin, Harisha Rajanala, Vincent L Cryns
PURPOSE: Despite robust antitumor activity in diverse preclinical models, TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists have not demonstrated efficacy in clinical trials, underscoring the need to identify agents that enhance their activity. We postulated that the metabolic stress induced by the diabetes drug metformin would sensitize breast cancer cells to TRAIL receptor agonists. METHODS: Human triple (estrogen receptor, progesterone receptor, and HER2)-negative breast cancer (TNBC) cell lines were treated with TRAIL receptor agonists (monoclonal antibodies or TRAIL peptide), metformin, or the combination...
March 21, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28243322/targeting-metabolic-remodeling-in-triple-negative-breast-cancer-in-a-murine-model
#4
Verónica García-Castillo, Eduardo López-Urrutia, Octavio Villanueva-Sánchez, Miguel Á Ávila-Rodríguez, Alejandro Zentella-Dehesa, Carlo Cortés-González, César López-Camarillo, Nadia J Jacobo-Herrera, Carlos Pérez-Plasencia
Background: Chemotherapy is the backbone of systemic treatment for triple negative breast cancer (TNBC), which is one of the most relevant breast cancers molecular types due to the ability of tumor cells to develop drug resistance, highlighting the urgent need to design newer and safer drug combinations for treatment. In this context, to overcome tumor cell drug resistance, we employed a novel combinatorial treatment including Doxorubicin, Metformin, and Sodium Oxamate (DoxMetOx). Such pharmacological combination targets indispensable hallmarks of cancer-related to aerobic glycolysis and DNA synthesis...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/27926515/metformin-and-propranolol-combination-prevents-cancer-progression-and-metastasis-in-different-breast-cancer-models
#5
María Rico, María Baglioni, Maryna Bondarenko, Nahuel Cesatti Laluce, Viviana Rozados, Nicolas André, Manon Carré, O Graciela Scharovsky, Mauricio Menacho Márquez
Discovery of new drugs for cancer treatment is an expensive and time-consuming process and the percentage of drugs reaching the clinic remains quite low.Drug repositioning refers to the identification and development of new uses for existing drugs and represents an alternative drug development strategy.In this work, we evaluated the antitumor effect of metronomic treatment with a combination of two repositioned drugs, metformin and propranolol, in triple negative breast cancer models.By in vitro studies with five different breast cancer derived cells, we observed that combined treatment decreased proliferation (P < 0...
January 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/27903149/obesity-and-breast-cancer-prognosis-evidence-challenges-and-opportunities
#6
Sao Jiralerspong, Pamela J Goodwin
Purpose To summarize the evidence of an association between obesity and breast cancer prognosis. Methods We reviewed the literature regarding overweight and obesity and breast cancer survival outcomes, overall and with regard to breast cancer subtypes, breast cancer therapies, biologic mechanisms, and possible interventions. We summarize our findings and provide clinical management recommendations. Results Obesity is associated with a 35% to 40% increased risk of breast cancer recurrence and death and therefore poorer survival outcomes...
December 10, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/26919310/metformin-attenuates-transforming-growth-factor-beta-tgf-%C3%AE-mediated-oncogenesis-in-mesenchymal-stem-like-claudin-low-triple-negative-breast-cancer
#7
Reema Wahdan-Alaswad, J Chuck Harrell, Zeying Fan, Susan M Edgerton, Bolin Liu, Ann D Thor
Mesenchymal stem-like/claudin-low (MSL/CL) breast cancers are highly aggressive, express low cell-cell adhesion cluster containing claudins (CLDN3/CLDN4/CLDN7) with enrichment of epithelial-to-mesenchymal transition (EMT), immunomodulatory, and transforming growth factor-β (TGF-β) genes. We examined the biological, molecular and prognostic impact of TGF-β upregulation and/or inhibition using in vivo and in vitro methods. Using publically available breast cancer gene expression databases, we show that upregulation and enrichment of a TGF-β gene signature is most frequent in MSL/CL breast cancers and is associated with a worse outcome...
2016: Cell Cycle
https://www.readbyqxmd.com/read/26561471/mechanism-of-metformin-action-in-mcf-7-and-mda-mb-231-human-breast-cancer-cells-involves-oxidative-stress-generation-dna-damage-and-transforming-growth-factor-%C3%AE-1-induction
#8
Poliana Camila Marinello, Thamara Nishida Xavier da Silva, Carolina Panis, Amanda Fouto Neves, Kaliana Larissa Machado, Fernando Henrique Borges, Flávia Alessandra Guarnier, Sara Santos Bernardes, Júlio Cesar Madureira de-Freitas-Junior, José Andrés Morgado-Díaz, Rodrigo Cabral Luiz, Rubens Cecchini, Alessandra Lourenço Cecchini
The participation of oxidative stress in the mechanism of metformin action in breast cancer remains unclear. We investigated the effects of clinical (6 and 30 μM) and experimental concentrations of metformin (1000 and 5000 μM) in MCF-7 and in MDA-MB-231 cells, verifying cytotoxicity, oxidative stress, DNA damage, and intracellular pathways related to cell growth and survival after 24 h of drug exposure. Clinical concentrations of metformin decreased metabolic activity of MCF-7 cells in the MTT assay, which showed increased oxidative stress and DNA damage, although cell death and impairment in the proliferative capacity were observed only at higher concentrations...
April 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/26236947/ampk-inhibits-mtdh-expression-via-gsk3%C3%AE-and-sirt1-activation-potential-role-in-triple-negative-breast-cancer-cell-proliferation
#9
COMPARATIVE STUDY
Paradesi Naidu Gollavilli, Anantha Koteswararao Kanugula, Rajeswari Koyyada, Santosh Karnewar, Praveen Kumar Neeli, Srigiridhar Kotamraju
Recent studies have highlighted the involvement of metadherin (MTDH), an oncogenic protein, in promoting cancer progression, metastasis and chemoresistance in many cancers including mammary carcinomas. However, the molecular regulation of MTDH is still not completely understood. In this study we document that AMP activated protein kinase (AMPK) activation-induced anti-proliferative effects are, in part, mediated by inhibiting MTDH expression in MDA-MB-231 and BT-549 triple negative breast cancer (TNBC) cells...
October 2015: FEBS Journal
https://www.readbyqxmd.com/read/25916213/association-of-diabetes-and-diabetes-treatment-with-incidence-of-breast-cancer
#10
Esther García-Esquinas, Elisabeth Guinó, Gemma Castaño-Vinyals, Beatriz Pérez-Gómez, Javier Llorca, Jone M Altzibar, Rosana Peiró-Pérez, Vicente Martín, Concepción Moreno-Iribas, Adonina Tardón, Francisco Javier Caballero, Montse Puig-Vives, Marcela Guevara, Tania Fernández Villa, Dolores Salas, Pilar Amiano, Trinidad Dierssen-Sotos, Roberto Pastor-Barriuso, María Sala, Manolis Kogevinas, Nuria Aragonés, Víctor Moreno, Marina Pollán
AIMS: The aim of this study was to evaluate the association of diabetes and diabetes treatment with risk of postmenopausal breast cancer. METHODS: Histologically confirmed incident cases of postmenopausal breast (N = 916) cancer were recruited from 23 Spanish public hospitals. Population-based controls (N = 1094) were randomly selected from primary care center lists within the catchment areas of the participant hospitals. ORs (95 % CI) were estimated using mixed-effects logistic regression models, using the recruitment center as a random effect term...
February 2016: Acta Diabetologica
https://www.readbyqxmd.com/read/25213330/metformin-induced-killing-of-triple-negative-breast-cancer-cells-is-mediated-by-reduction-in-fatty-acid-synthase-via-mirna-193b
#11
Reema S Wahdan-Alaswad, Dawn R Cochrane, Nicole S Spoelstra, Erin N Howe, Susan M Edgerton, Steven M Anderson, Ann D Thor, Jennifer K Richer
The anti-diabetic drug metformin (1,1-dimethylbiguanide hydrochloride) reduces both the incidence and mortality of several types of cancer. Metformin has been shown to selectively kill cancer stem cells, and triple-negative breast cancer (TNBC) cell lines are more sensitive to the effects of metformin as compared to luminal breast cancer. However, the mechanism underlying the enhanced susceptibility of TNBC to metformin has not been elucidated. Expression profiling of metformin-treated TNBC lines revealed fatty acid synthase (FASN) as one of the genes most significantly downregulated following 24 h of treatment, and a decrease in FASN protein was also observed...
December 2014: Hormones & Cancer
https://www.readbyqxmd.com/read/25196138/the-biguanides-metformin-and-phenformin-inhibit-angiogenesis-local-and-metastatic-growth-of-breast-cancer-by-targeting-both-neoplastic-and-microenvironment-cells
#12
Stefania Orecchioni, Francesca Reggiani, Giovanna Talarico, Patrizia Mancuso, Angelica Calleri, Giuliana Gregato, Valentina Labanca, Douglas M Noonan, Katiuscia Dallaglio, Adriana Albini, Francesco Bertolini
The human white adipose tissue (WAT) contains progenitors with cooperative roles in breast cancer (BC) angiogenesis, local and metastatic progression. The biguanide Metformin (Met), commonly used for Type 2 diabetes, might have activity against BC and was found to inhibit angiogenesis in vivo. We studied Met and another biguanide, phenformin (Phe), in vitro and in vivo in BC models. In vitro, biguanides activated AMPK, inhibited Complex 1 of the respiratory chain and induced apoptosis of BC and WAT endothelial cells...
March 15, 2015: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/24829621/advances-in-preventive-therapy-for-estrogen-receptor-negative-breast-cancer
#13
REVIEW
Beate C Litzenburger, Powel H Brown
Preventing breast cancer is an effective strategy for reducing breast cancer deaths. The purpose of chemoprevention (also termed preventive therapy) is to reduce cancer incidence by use of natural, synthetic, or biological agents. The efficacy of tamoxifen, raloxifene, and exemestane as preventive therapy against estrogen-receptor (ER)-positive breast cancer is well established for women at increased risk for breast cancer. However, because breast cancer is a heterogeneous disease, distinct preventive approaches may be required for effective prevention of each subtype...
2014: Current Breast Cancer Reports
https://www.readbyqxmd.com/read/24774412/long-term-use-of-metformin-and-the-molecular-subtype-in-invasive-breast-carcinoma-patients-a-retrospective-study-of-clinical-and-tumor-characteristics
#14
Nikola Besic, Nika Satej, Ivica Ratosa, Andreja Gojkovic Horvat, Tanja Marinko, Barbara Gazic, Rok Petric
BACKGROUND: Metformin may exhibit inhibitory effects on cancer cells by inhibiting mTOR signaling pathway. The aim of our retrospective study was to examine if patients with breast carcinoma (BC) and diabetes mellitus (DM) receiving metformin have a lower stage of carcinoma in comparison to patients not receiving metformin, and if the use of metformin correlates with the molecular subtype of BC. METHODS: A chart review of 253 patients with invasive BC and DM (128 on metformin and 125 not on metformin) was performed...
2014: BMC Cancer
https://www.readbyqxmd.com/read/24716971/lack-of-metformin-effects-on-different-molecular-subtypes-of-breast-cancer-under-normoglycemic-conditions-an-in-vitro-study
#15
Sanambar Sadighi, Saeid Amanpour, Bita Behrouzi, Zhinoos Khorgami, Samad Muhammadnejad
BACKGROUND: In the past few years, a considerable number of preclinical studies have been proposed metformin as a potential anticancer agent, but some of these studies suffer from a number of methodological limitations such as assessment of cytotoxicity in the presence of supraphysiological glucose concentrations or applying suprapharmacological levels of the drug. These objections have limited the translation of published preclinical data to the clinical setting. The present study aimed to investigate direct anticancer effects of metformin on different molecular subtypes of breast cancer with pharmacological concentrations and under normoglycemic conditions in vitro...
2014: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/24462945/the-anti-proliferative-effect-of-metformin-in-triple-negative-mda-mb-231-breast-cancer-cells-is-highly-dependent-on-glucose-concentration-implications-for-cancer-therapy-and-prevention
#16
Beshay N M Zordoky, Diana Bark, Carrie L Soltys, Miranda M Sung, Jason R B Dyck
BACKGROUND: Metformin has been shown to have a strong anti-proliferative effect in many breast cancer cell lines, mainly due to the activation of the energy sensing kinase, AMP-activated protein kinase (AMPK). MDA-MB-231 cells are aggressive and invasive breast cancer cells that are known to be resistant to several anti-cancer agents as well as to the anti-proliferative effect of metformin. As metformin is a glucose lowering drug, we hypothesized that normoglycemia will sensitize MDA-MB-231 cells to the anti-proliferative effect of metformin...
June 2014: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/24240433/direct-inhibition-of-hexokinase-activity-by-metformin-at-least-partially-impairs-glucose-metabolism-and-tumor-growth-in-experimental-breast-cancer
#17
Cecilia Marini, Barbara Salani, Michela Massollo, Adriana Amaro, Alessia Isabella Esposito, Anna Maria Orengo, Selene Capitanio, Laura Emionite, Mattia Riondato, Gianluca Bottoni, Cinzia Massara, Simona Boccardo, Marina Fabbi, Cristina Campi, Silvia Ravera, Giovanna Angelini, Silvia Morbelli, Michele Cilli, Renzo Cordera, Mauro Truini, Davide Maggi, Ulrich Pfeffer, Gianmario Sambuceti
Emerging evidence suggests that metformin, a widely used anti-diabetic drug, may be useful in the prevention and treatment of different cancers. In the present study, we demonstrate that metformin directly inhibits the enzymatic function of hexokinase (HK) I and II in a cell line of triple-negative breast cancer (MDA-MB-231). The inhibition is selective for these isoforms, as documented by experiments with purified HK I and II as well as with cell lysates. Measurements of (18)F-fluoro-deoxyglycose uptake document that it is dose- and time-dependent and powerful enough to virtually abolish glucose consumption despite unchanged availability of membrane glucose transporters...
November 15, 2013: Cell Cycle
https://www.readbyqxmd.com/read/24221746/clinical-studies-examining-the-impact-of-obesity-on-breast-cancer-risk-and-prognosis
#18
REVIEW
Rishi Jain, Howard D Strickler, Eugene Fine, Joseph A Sparano
Obesity is associated with an increased risk of breast cancer, and increased risk of recurrence in women who develop breast cancer. Evidence suggests that the risk of estrogen-receptor (ER)-positive breast cancer is increased in obese postmenopausal women, whereas in premenopausal women the risk of triple negative breast cancer is increased. Nonetheless, the presence of obesity at diagnosis, and possibly weight gain after diagnosis, may independently contribute to an individual's risk of recurrence of both pre- and postmenopausal breast cancer...
December 2013: Journal of Mammary Gland Biology and Neoplasia
https://www.readbyqxmd.com/read/24107633/glucose-promotes-breast-cancer-aggression-and-reduces-metformin-efficacy
#19
Reema Wahdan-Alaswad, Zeying Fan, Susan M Edgerton, Bolin Liu, Xin-Sheng Deng, Sigrid Salling Arnadottir, Jennifer K Richer, Steven M Anderson, Ann D Thor
Metformin treatment has been associated with a decrease in breast cancer risk and improved survival. Metformin induces complex cellular changes, resulting in decreased tumor cell proliferation, reduction of stem cells, and apoptosis. Using a carcinogen-induced rodent model of mammary tumorigenesis, we recently demonstrated that overfeeding in obese animals is associated with a 50% increase in tumor glucose uptake, increased proliferation, and tumor cell reprogramming to an "aggressive" metabolic state. Metformin significantly inhibited these pro-tumorigenic effects...
December 15, 2013: Cell Cycle
https://www.readbyqxmd.com/read/24091632/direct-inhibition-of-hexokinase-activity-by-metformin-at-least-partially-impairs-glucose-metabolism-and-tumor-growth-in-experimental-breast-cancer
#20
Cecilia Marini, Barbara Salani, Michela Massollo, Adriana Amaro, Alessia Esposito, Anna Maria Orengo, Selene Capitanio, Laura Emionite, Mattia Riondato, Gianluca Bottoni, Cinzia Massara, Simona Boccardo, Marina Fabbi, Cristina Campi, Silvia Ravera, Giovanna Angelini, Silvia Morbelli, Michele Cilli, Renzo Cordera, Mauro Truini, Davide Maggi, Ulrich Pfeffer, Gianmario Sambuceti
Emerging evidence suggests that metformin, a widely used anti-diabetic drug, may be useful in the prevention and treatment of different cancers. In the present study, we demonstrate that metformin directly inhibits the enzymatic function of hexokinase (HK) I and II in a cell line of triple-negative breast cancer (MDA-MB-231). The inhibition is selective for these isoforms, as documented by experiments with purified HK I and II as well as with cell lysates. Measurements of (18)F-fluoro-deoxyglycose uptake document that it is dose- and time-dependent and powerful enough to virtually abolish glucose consumption despite unchanged availability of membrane glucose transporters...
September 19, 2013: Cell Cycle
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