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Metformin and triple negative breast cancer

Inês Amaral, Cláudia Silva, Ana Correia-Branco, Fátima Martel
This work aimed to investigate the effect of metformin on cellular glucose uptake and metabolism by breast cancer cells, as a mechanism contributing to its anticancer properties. Estrogen and progesterone receptor-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cell lines were used as in vitro models of breast cancer. Short-term (26 min) exposure of MCF-7 and MDA-MB-231 cells to metformin inhibited uptake of3 H-deoxy-D-glucose (3 H-DG). In contrast, long-term (24 h) exposure to metformin (5 μM-1 mM) concentration-dependently increased3 H-DG uptake in both cell lines...
March 15, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Balraj Singh, Vanessa N Sarli, Laura J Washburn, Milan R Raythatha, Anthony Lucci
We previously described a strategy for selecting highly adaptable rare triple-negative breast cancer (TNBC) cells based on their ability to survive a severe and prolonged metabolic challenge, e.g., a lack of glutamine. We hypothesized that metabolically adaptable (MA) cancer cells selected from the SUM149 cell line in this manner have the capacity to survive a variety of challenges that postulated "decathlon winner" cancer cells must survive to succeed in metastasis. These MA cells were resistant to glutaminase inhibitor CB-839, as predicted from their ability to proliferate without exogenous glutamine...
February 16, 2018: Oncotarget
Maria Eduarda Azambuja Amaral, Laura Roesler Nery, Carlos Eduardo Leite, Walter Filgueira de Azevedo Junior, Maria Martha Campos
Background Breast cancer is highly prevalent among women worldwide. It is classified into three main subtypes: estrogen receptor positive (ER+), human epidermal growth factor receptor 2 positive (HER2+), and triple negative breast cancer (TNBC). This study has evaluated the effects of aspirin and metformin, isolated or in a combination, in breast cancer cells of the different subtypes. Methods The breast cancer cell lines MCF-7, MDA-MB-231, and SK-BR-3 were treated with aspirin and/or metformin (0.01 mM - 10 mM); functional in vitro assays were performed...
February 2, 2018: Investigational New Drugs
Peiguo Shi, Wenjing Liu, Tala, Haixia Wang, Fubing Li, Hailin Zhang, Yingying Wu, Yanjie Kong, Zhongmei Zhou, Chunyan Wang, Wenlin Chen, Rong Liu, Ceshi Chen
Out of the breast cancer subtypes, triple-negative breast cancer (TNBC) has the poorest prognosis without effective targeted therapies. Metformin, a first-line drug for type 2 diabetes mellitus, was demonstrated to target breast cancer stem cells selectively. However, the efficiency and the mechanism of action of metformin in TNBC are unclear. In this study, we demonstrated that metformin decreased the percentage of TNBC stem cells partially through the downregulation of the expression of the stem cell transcription factor Krüppel-like factor 5 (KLF5) and its downstream target genes, such as Nanog and FGF-BP1, in TNBC cell lines...
2017: Cell Discovery
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)...
April 18, 2017: Oncotarget
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
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...
June 2017: Breast Cancer Research and Treatment
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
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
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
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
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
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
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
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
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
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
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...
April 28, 2014: BMC Cancer
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
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
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