Showing papers by "Javier A. Menendez published in 2010"
Carlos III Health Institute1, University of Chieti-Pescara2, Spanish National Research Council3, Autonomous University of Barcelona4, Tufts University5, University of Seville6, Marche Polytechnic University7, University of Naples Federico II8, University of Jaén9, Mario Negri Institute for Pharmacological Research10, French Institute of Health and Medical Research11, University of Zaragoza12, National and Kapodistrian University of Athens13, University of Córdoba (Spain)14, University of Copenhagen15, University of Granada16, University of Las Palmas de Gran Canaria17, University of Bari18, University of Paris19
TL;DR: Results of case-control and cohort studies suggest that MUFA intake including OO is associated with a reduction in cancer risk, and the concept that the OO-rich MedDiet is compatible with healthier aging and increased longevity is consistent.
Abstract: Olive oil (OO) is the most representative food of the traditional Mediterranean Diet (MedDiet). Increasing evidence suggests that monounsaturated fatty acids (MUFA) as a nutrient, OO as a food, and the MedDiet as a food pattern are associated with a decreased risk of cardiovascular disease, obesity, metabolic syndrome, type 2 diabetes and hypertension. A MedDiet rich in OO and OO per se has been shown to improve cardiovascular risk factors, such as lipid profiles, blood pressure, postprandial hyperlipidemia, endothelial dysfunction, oxidative stress, and antithrombotic profiles. Some of these beneficial effects can be attributed to the OO minor components. Therefore, the definition of the MedDiet should include OO. Phenolic compounds in OO have shown antioxidant and anti-inflammatory properties, prevent lipoperoxidation, induce favorable changes of lipid profile, improve endothelial function, and disclose antithrombotic properties. Observational studies from Mediterranean cohorts have suggested that dietary MUFA may be protective against age-related cognitive decline and Alzheimer's disease. Recent studies consistently support the concept that the OO-rich MedDiet is compatible with healthier aging and increased longevity. In countries where the population adheres to the MedDiet, such as Spain, Greece and Italy, and OO is the principal source of fat, rates of cancer incidence are lower than in northern European countries. Experimental and human cellular studies have provided new evidence on the potential protective effect of OO on cancer. Furthermore, results of case-control and cohort studies suggest that MUFA intake including OO is associated with a reduction in cancer risk (mainly breast, colorectal and prostate cancers).
474 citations
TL;DR: The notion that, by acting as an efficient caloric restriction mimetic, metformin enhanced intrinsic capacity of mitotically competent cells to self-maintenance and repair (hormesis) might trigger counterintuitive detrimental effects of hormesis is presented.
Abstract: In the early 1970s, Professor Vladimir Dilman originally developed the idea that antidiabetic biguanides may be promising as geroprotectors and anticancer drugs ("metabolic rehabilitation"). In the early 2000s, Anisimov´s experiments revealed that chronic treatment of female transgenic HER2-/neu mice with metformin significantly reduced the incidence and size of mammary adenocarcinomas and increased the mean latency of the tumors. Epidemiological studies have confirmed that metformin, but not other anti-diabetic drugs, significantly reduces cancer incidence and improves cancer patients' survival in type 2 diabetics. At present, pioneer work by Dilman & Anisimov at the Petrov Institute of Oncology (St. Petersburg, Russia) is rapidly evolving due to ever-growing preclinical studies using human tumor-derived cultured cancer cells and animal models. We herein critically review how the antidiabetic drug metformin is getting reset to metabolically fight cancer. Our current perception is that metformin may co...
214 citations
TL;DR: It is proposed that metformin, by weakening the ability of TGFb signaling to fully induce mesenchymal cell states in a variety of pathological processes including fibrosis, molecularly behaves as a bona fide anti-aging modality.
Abstract: Transforming Growth Factor-b (TGFb) is a major driving force of the Epithelial-to-Mesenchymal (EMT) genetic program, which becomes overactive in the pathophysiology of many age-related human diseases. TGFb-driven EMT is sufficient to generate migrating cancer stem cells by directly linking the acquisition of cellular motility with the maintenance of tumor-initiating (stemness) capacity. Chronic diseases exhibiting excessive fibrosis can be caused by repeated and sustained infliction of TGFb-driven EMT, which increases collagen and extracellular matrix synthesis. Pharmacological prevention and/or reversal of TGFb-induced EMT may therefore have important clinical applications in the management of cancer metastasis as well as in the prevention and/or treatment of end-state organ failures. Earlier studies from our group have revealed that clinically-relevant concentrations of the biguanide derivative metformin, the most widely used oral agent to lower blood glucose concentration in patients with type 2 di...
211 citations
TL;DR: Findings provide strong motivation for the continued molecular understanding and clinical development of metformin as a non-toxic therapeutic aimed to interdict the breast cancer stem cell phenotype by targeting EMT, a molecular process that is central to the ontogenesis of the breast Cancer stem cell molecular signature.
Abstract: The sole overexpression of pivotal regulators of the embryonic Epithelial-Mesenchymal Transition (EMT) genetic program ("EMT status") may be sufficient to efficiently drive the ontogeny of the breast cancer stem cell molecular signature independently of changes in EMT functioning ("EMT phenotype"). Using basal-like breast cancer models naturally enriched in either CD44(pos)CD24(low/neg) or CD44(pos)CD24(pos) tumor-initiating cell populations we herein illustrate that non-cytotoxic concentrations of the anti-diabetic drug metformin efficiently impedes the ontogeny of generating the stem cell phenotype by transcriptionally repressing the stem cell property EMT. Metformin treatment dynamically regulated the CD44(pos)CD24(neg/low) breast cancer stem cell immunophenotype, transcriptionally reprogrammed cells through decreased expression of key drivers of the EMT machinery including the transcription factors ZEB1, TWIST1 and SNAI2 (Slug) and the pleiotrophic cytokines TGFβs, and lastly impeded the propensity of breast cancer stem cells to form multicellular "microtumors" in non-adherent and non-differentiating conditions (i.e., "mammospheres"). These findings, altogether, provide strong motivation for the continued molecular understanding and clinical development of metformin as a non-toxic therapeutic aimed to interdict the breast cancer stem cell phenotype by targeting EMT, a molecular process that is central to the ontogenesis of the breast cancer stem cell molecular signature.
193 citations
TL;DR: The ability of HER2 to supercharge lipogenesis while averting lipotoxicity supports the notion that best adapted cancer phenotypes are addicted to oncogenic lipid metabolism for cell proliferation and survival.
140 citations
TL;DR: The occurrence of correlations between the phenolic composition of EVOO-derived crude phenolic extracts and their anti-proliferative abilities toward human breast cancer-derived cell lines is described.
138 citations
TL;DR: Olive leaf extracts exhibited dose-dependent inhibitory effects on the metabolic status (cell viability) of three breast cancer models in vitro, and warrant further investigation at the structure–function molecular level to definitely establish the anticancer value of these phytochemicals.
Abstract: In this work, high-performance liquid chromatography (HPLC) coupled to electrospray time-of-flight mass spectrometry (ESI-TOF-MS) and electrospray ion trap multiple-stage tandem mass spectrometry (ESI-IT-MS2) has been applied to screen phenolic compounds in olive leaf extracts. The use of a small particle size C18 column (1.8 μm) provided great resolution and made separation of a lot of isomers possible. The structural characterization was based on accurate mass data obtained by ESI-TOF-MS, and the nature of fragmentation ions were further confirmed by ESI-IT-MS2 when possible. In addition, we employed tetrazolium salt (MTT)-based assays to assess the effects of olive leaf extracts on the growth of human tumor-derived cells. Upon this approach, we achieved an accurate profile of olive leaf phenolics along with the identification of several important isomers of secoiridoids and flavonoids. This will allow a better understanding of the complete composition of olive-leaf-bioactive compounds as well as their involvement in Olea europaea L. biochemical pathways. Importantly, olive leaf extracts exhibited dose-dependent inhibitory effects on the metabolic status (cell viability) of three breast cancer models in vitro. Since the tumoricidal activity of the extracts should be mainly attributed to the identified olive leaf phenolics, these findings warrant further investigation at the structure–function molecular level to definitely establish the anticancer value of these phytochemicals.
120 citations
TL;DR: A rapid resolution liquid chromatography coupled to electrospray ionization time-of-flight mass spectrometry (RRLC-ESI-TOF-MS) method followed by tetrazolium salt (MTT)-based cell viability assays was developed for qualitative and quantitative classification of extra virgin olive oil varieties by phenolic and other polar compound contents as well as for rapid characterization of putative cytotoxic activities against human cancer cells.
Abstract: The aim of this work was to develop a rapid resolution liquid chromatography coupled to electrospray ionization time-of-flight mass spectrometry (RRLC-ESI-TOF-MS) method followed by tetrazolium salt (MTT)-based cell viability assays for qualitative and quantitative classification of extra virgin olive oil (EVOO) varieties by phenolic and other polar compound contents as well as for rapid characterization of putative cytotoxic activities against human cancer cells. Five different Spanish EVOO varieties were analyzed, and RRLC-ESI-TOF-MS method was applied for qualitative and quantitative identification of most important phenolic compounds. We finally employed MTT-based cell viability protocol to assess the effects of crude EVOO phenolic extracts (PEs) on the metabolic status of cultured SKBR3 human breast cancer cells. MTT-based cell viability assays revealed a wide range of breast cancer cytotoxic potencies among individual crude PE obtained from EVOO monovarietals. Remarkably, breast cancer cell sensitivity to crude EVOO-PEs was up to 12 times higher in secoiridoids enriched-PE than in secoiridoids-low/null EVOO-PE.
89 citations
TL;DR: Investigation of the unique histogenesis of the basal/HER2+ phenotype in breast carcinomas and low-scale proteomic approaches in JIMT-1 cells to develop biomarker signatures that may differentiate trastuzumab-responsive from non-responsive tumors validate the notion that identification of basal- like immunophenotypes and/or basal-like molecular signatures within HER2+ breast carcinoma may provide rapid means to define subgroups of breast cancer patients likely to display resistance to trast
Abstract: Pioneering clinical studies in de novo refractoriness to the anti-HER2 monoclonal antibody trastuzumab have suggested that HER2 gene-amplification can take place also in a basal-like molecular background to generate basal/HER2+ tumors intrinsically resistant to trastuzumab. Here, we first investigated the unique histogenesis of the basal/HER2+ phenotype in breast carcinomas. The presence of basal CK5/CK6 cytokeratin expression in HER2+ tumors revealed a significant overlap in the histological features of HER2+/CK5/6+ and basal-like breast carcinomas. Basal/HER2+ tumors were typically poorly differentiated, high-grade invasive ductal carcinomas with large geographic necrosis, pushing margins of invasion, syncytial arrangement of tumor cells, ribbon- or festoon-like architecture, squamous metaplasia, stromal lymphocytic infiltrates, high mitotic index and strong p53 positivity. Secondly, we performed low-scale proteomic approaches in JIMT-1 cells, a unique model of HER2-gene amplified trastuzumab-resistant breast carcinoma with a basal-like phenotype, to develop biomarker signatures that may differentiate trastuzumab-responsive from non-responsive tumors. When applying antibody-based array technology to the extracellular milieu of trastuzumab-refractory JIMT-1 and trastuzumab-sensitive SKBR3 cell cultures, JIMT-1 cells were found to secrete higher amounts of several growth factors including amphiregulin, EGF, IGFBP-6, PDGF-AA, neurotrophins, TGFbeta and VEGF. Semi-quantitative signaling node multi-target sandwich ELISAs revealed that JIMT-1 cells drastically overactivate RelA, the prosurvival subunit of NF-kappaB as compared to trastuzumab-sensitive luminal/HER2+ SKBR3 cells. When simultaneously assessing the activation status of 42 receptor tyrosine kinases (RTK) using a human phospho-RTK array, JIMT-1 cells were found to constitutively display hyperactivation of the insulin-like growth factor-I receptor (IGF-1R). High-content immunofluorescence imaging revealed that activated IGF-1R mainly localized at focal adhesion-like structures in JIMT-1 cells. In vitro wound healing assays suggested that this functional reorganization of the JIMT-1 cytoskeletal reorganization may account for an exacerbated trastuzumab-refractory 'migratogenic' phenotype. Forthcoming studies should validate the notion that identification of basal-like immunophenotypes and/or basal-like molecular signatures within HER2+ breast carcinomas may provide rapid means to define subgroups of breast cancer patients likely to display resistance to trastuzumab ab initio.
68 citations
66 citations
TL;DR: Intrinsic genetic plasticity to efficiently drive the emergence of the CD44(pos)/CD24(neg/low) mesenchymal phenotype may account for de novo resistance to HER2 targeting therapies in basal-like BC carrying HER2 gene amplification.
TL;DR: The multifaceted and redundant mechanisms through which metformin-reprogrammed energy metabolism at both the organismal and cellular levels constitutes a novel and valuable strategy to prevent and treat breast cancer disease are illustrated.
Abstract: A whole new area of investigation has emerged recently with regards to the anti-diabetic drug metformin and breast cancer. Metformins anti-breast cancer actions, observed in population studies, in rodents and in cultured tumour cells, are especially encouraging because they attack not only the most common bulk of the tumour cells but also the more rare tumour-initiating stem cells. Here, we illustrate the multifaceted and redundant mechanisms through which metformin-reprogrammed energy metabolism at both the organismal and cellular levels constitutes a novel and valuable strategy to prevent and treat breast cancer disease.
TL;DR: The results suggest that circulating FASN is a biomarker of overnutrition-induced insulin resistance that could provide diagnostic and prognostic advantages by providing insights on the individualized metabolic stress.
Abstract: CONTEXT—Circulating fatty acid synthase (FASN) is a biomarker of metabolically demanding human diseases. The aim of this study was to determine whether circulating FASN could be a biomarker of overnutrition-induced metabolic stress and insulin resistance in common metabolic disorders. RESEARCH DESIGN AND METHODS—Circulating FASN was evaluated in two cross-sectional studies in association with insulin sensitivity and in four longitudinal studies investigating the effect of diet- and surgery-induced weight loss, physical training, and adipose tissue expansion using peroxisome proliferator–activated receptor agonist rosiglitazone on circulating FASN. RESULTS—Age- and BMI-adjusted FASN concentrations were significantly increased in association with obesity-induced insulin resistance in two independent cohorts. Both visceral and subcutaneous FASN expression and protein levels correlated inversely with extracellular circulating FASN (P 0.63; P 0.0001), suggesting that circulating FASN is linked to depletion of intracellular FASN. Improved insulin sensitivity induced by therapeutic strategies that decreased fat mass (diet induced, surgery induced, or physical training) all led to decreased FASN levels in blood (P values between 0.02 and 0.04). To discriminate whether this was an effect related to insulin sensitization, we also investigated the effects of rosiglitazone. Rosiglitazone did not lead to significant changes in circulating FASN concentration. CONCLUSIONS—Our results suggest that circulating FASN is a biomarker of overnutrition-induced insulin resistance that could provide diagnostic and prognostic advantages by providing insights on the individualized metabolic stress. Diabetes 59: 1506–1511, 2010
TL;DR: The ability of metformin to suppress the oncogene, metastasis promoter and breast cancer stem cell marker CD24 may open a novel molecular avenue in the therapeutic management of highly-metastastic subgroups of triple-negative (basal-like) breast cancers naturally enriched with CD44posCD24pos tumor-initiating cell populations.
Abstract: CD24, a mucin-like adhesion molecule that enhances the metastatic potential of malignant cells, has been suggested to be a marker of poor prognosis in breast carcinomas. The tumor-initiating potential of CD44posCD24pos cell populations has been recently recognized and, accordingly, distant metastases are largely composed of CD24-positive cells in breast cancer patients refractory to treatment. Therefore, new therapeutic strategies aimed at down-regulating CD24 may negatively regulate the dissemination of tumor cells and formation of metastasis. Here, we reveal that suppression of CD24 protein expression is a crucial event in the molecular mechanisms underlying the growth-inhibitory effects of the anti-diabetic drug metformin in MDA-MB-468 triple-negative (basal-like) breast cancer cells. First, we confirmed that, among the different molecular classes of breast cancer, basal-like breast cancer cells were significantly more sensitive to the growth-inhibitory effects of metformin. Second, we observed a positive correlation between the growth inhibitory activity of metformin and the relative enrichment in cells bearing the CD44posCD24pos immunophenotype. Third, high-content indirect immunofluorescence imaging assays revealed that CD24 protein levels were drastically decreased in the presence of growth-inhibitory concentrations of metformin. Fourth, to preliminary assess the clinical relevance of metformin's anti-CD24 effects we took advantage of the recently developed ROCK online interface (http://rock.icr.ac.uk/), a publicly accessible portal that allows rapid integration of breast cancer functional and molecular profiling datasets. When we evaluated the impact of CD24 expression on distant metastasis-free survival (DMFS) in microarray gene expression breast cancer datasets, Kaplan-Meier survival analyses and log-rank tests comparing DMSF for CD24-high and CD24-low breast carcinomas revealed that patients with CD24-high tumors tended to have a shorter DMFS. These findings, altogether, suggest that the ability of metformin to suppress the oncogene, metastasis promoter and breast cancer stem cell marker CD24 may open a novel molecular avenue in the therapeutic management of highly-metastastic subgroups of triple-negative (basal-like) breast cancers naturally enriched with CD44posCD24pos tumor-initiating cell populations.
TL;DR: HS14 gene expression and protein levels were up-regulated at the early stages of differentiation of human pre-adipocytes as well as for 3T3-L1 cells, suggesting that hS14 is involved in human adipogenesis, but inversely related to obesity and OM fat accumulation.
Abstract: Thyroid hormone responsive Spot 14 increases during differentiation of human adipocytes and its expression is down-regulated in obese subjects
TL;DR: Serum FASN concentration is significantly increased in HIV-infected individuals and the release of FASn into the circulation is further enhanced in patients who are co- Infected with HCV, suggesting that this indicator should be explored to monitor the effect of viral infections on disease progression and survival.
Abstract: Background: Fatty acid synthase (FASN) is an enzyme synthesized by the liver and plays an important role in lipogenesis The present study aimed to investigate whether serum FASN concentration may provide a direct link between HIV and/or HCV viral infections and lipid metabolic disorders commonly observed in HIV/HCV-infected patients Methods: We evaluated serum FASN concentration in 191 consecutive HIV-infected patients in the absence or presence of HCV co-infection For comparison, 102 uninfected controls were included Metabolic and inflammatory phenotype was also compared with respect to the presence of HCV co-infection Results: Serum FASN concentration was significantly higher in HIV-infected patients than in healthy participants and HCV co-infected patients showed higher levels than those without co-infection Levels were also affected by treatment regimen, but marginally influenced by virological variables Insulin concentration was the sole variable among metabolic parameters that demonstrated a significant correlation with serum FASN concentrations Serum alanine aminotransferase (ALT) values correlated significantly with serum FASN concentration and provided the best discrimination with respect to the presence or absence of HCV co-infection In multivariate analysis, only ALT, monocyte chemoattractant protein-1 (MCP-1) and the presence of antiretroviral treatment regimen significantly contributed to explain serum FASN concentration in HIV/HCV co-infected patients Conclusion: Serum FASN concentration is significantly increased in HIV-infected individuals The release of FASN into the circulation is further enhanced in patients who are co-infected with HCV Subsequent studies should explore the usefulness of this indicator to monitor the effect of viral infections on disease progression and survival
TL;DR: C cultured human cancer cells might be used as reliable models to test the ability of antiaging interventions for promoting the initiation and maintenance of self-renewing divisions and to investigate if antiaging benefits from caloric restriction mimetics might relate to their ability to epigenetically reprogram stemness while prolonging the capacity of stem-like cell states to proliferate, differentiate, and replace mature cells in adult aging tissues.
Abstract: Networks of oncogenes and tumor suppressor genes that control cancer cell proliferation also regulate stem cell renewal and possibly stem cell aging. Because (de)differentiation processes might dictate tumor cells to retrogress to a more stem-like state in response to aging-relevant epigenetic and/or environmental players, we recently envisioned that cultured human cancer cells might be used as reliable models to test the ability of antiaging interventions for promoting the initiation and maintenance of self-renewing divisions. Cancer cell lines naturally bearing undetectable amounts of stem/progenitor-like cell populations were continuously cultured in the presence of the caloric restriction mimetic metformin for several months. Microarray technology was employed to profile expression of genes related to the identification, growth, and differentiation of stem cells. Detection of functionally related gene groups using a pathway analysis package provided annotated genetic signatures over- and unde...
TL;DR: Serum HER-2 concentrations might be implicated in the pathophysiology of insulin resistance and associated comorbidities in healthy and obese subjects.
Abstract: Background: HER2/neu is a member of the epidermal growth factor receptor family easily detectable in the serum of cancer patients. We aimed to evaluate circulating HER-2 concentrations in association with insulin resistance in healthy and obese subjects. Methods: Insulin sensitivity (minimal model) and serum HER-2 concentrations were evaluated in a cross sectional study in men (cohort 1, n = 167) and longitudinally after weight loss in obese subjects (cohort 2, n = 30). Results: Serum HER-2 concentrations were positively associated with BMI and waist circumference (both r = 0.18, p = 0.02), post-load glucose (r = 0.28, p = 0.001) and fasting triglycerides (r = 0.26, p = 0.001); and negatively associated with insulin sensitivity (r = -0.29, p = 0.002, n = 109). Subjects with type 2 diabetes showed significantly increased soluble serum HER-2 concentrations. In different multivariate regression models, fasting triglycerides emerged as the factor that independently contributed to 10-11% of serum HER-2 variance. Serum HER-2 concentrations correlated significantly with fasting triglycerides and insulin sensitivity index in subjects from cohort 2. Weight loss led to a significant decrease of serum HER-2 concentrations. The change in serum HER-2 concentrations were significantly associated with the change in percent body fat and fasting triglycerides in young (below the median age of the cohort) subjects. Conclusions: Serum HER-2 concentrations might be implicated in the pathophysiology of insulin resistance and associated comorbidities.
TL;DR: It is suggested that defective autophagy that occurs upon loss of ATG6/BECN1 may lead to cell death in trastuzumab-treated ERBB2-positive cells bearing competent apoptosis or senescence pathways, and in agreement with Negri’s suggestion, the anti-ERBB2 monoclonal antibody trastudumab is added to the growing list of molecularly targeted therapeutics that can trigger a pro-survival function of
Abstract: Negri et al. (2010) have recently conducted pioneering studies revealing for the first time that a significant association between loss of ATG6/ BECN1—a haploinsufficient tumor suppressor that codes for a phylogenetically conserved protein essential for macroautophagy (Liang et al., 1999)— and ERBB2 oncogene amplification (both on 17q21) takes place in a subset of human breast carcinomas. Moreover, ATG6/BECN1 loss was found to predict better responses to the anti-ERBB2 monoclonal antibody trastuzumab (Herceptin) alone or in combination with other drugs. Although the authors acknowledge that, because the small sample size of the study (n 1⁄4 30), their findings should be interpreted as hypothesis-generating and confirmed on larger annotated cohorts of uniformly treated breast cancer patients, they suggest that a previously unrecognized significant correlation between ATG6/BECN1 allele deletion and ERBB2 amplification can be particularly relevant for both biological characterization and rational design of treatments for ERBB2-overexpressing breast carcinomas (Negri et al., 2010). Given that autophagy defects have been repeatedly shown to be associated with genome instability in the form of gene amplification, Negri et al. have suggested that ATG6/BECN1 loss might favor and contribute to ERBB2 gene amplification as well as to alterations in the ERBB2 downstream effectors PI3K and PTEN. Because the main predictors of trastuzumab response in both preclinical and clinical settings are ERBB2 gene amplification and the status of PI3K/PTEN (Saal et al., 2005; Berns et al., 2007; Park and Davidson, 2007), Negri et al. (2010) have suggested also that ATG6/ BECN1 loss may represent a novel positive therapeutic predictor in trastuzumab-based breast cancer treatment regimens. In agreement with Negri’s suggestion that defective autophagy that occurs upon loss of ATG6/BECN1 may lead to cell death in trastuzumab-treated ERBB2-positive cells bearing competent apoptosis or senescence pathways, we recently added the anti-ERBB2 monoclonal antibody trastuzumab to the growing list of molecularly targeted therapeutics that can trigger a pro-survival function of autophagy in ERBB2-dependent human breast carcinoma cells (Vazquez-Martin et al., 2009). We established that autophagic cell death (APCD; also referred to as active cell death II [ACDII] –which occurs following extreme autophagic degradation associated with exposure to several cancer therapies (Kondo and Kondo, 2006)—was not an obligatory outcome of trastuzumab-induced autophagy. Rather, our studies confirmed that activation of basal autophagy was causally related to the acquisition of trastuzumab resistance as ‘‘protective autophagy’’ actively maintained trastuzumab refractoriness in ERBB2-positive breast cancer cells (Vazquez-Martin et al., 2009). Cheng et al. (2010) have recently confirmed and expanded the cytoprotective effect of autophagy in breast cancer cells subjected to growth factor inhibition imposed by mono-EGFR (gefitinib), mono-ERBB2 (trastuzumab), and dual EGFR/ERBB2 (lapatinib) inhibitors. The findings by Negri et al. (2010) provide a novel scenario to explain a counterintuitive differential role of the general mechanism of autophagy (i.e., reduced autophagy represents an oncogenic event that actively contributes to tumor progression; enhanced autophagy constitutes a pro-survival molecular strategy that promotes tumor cell survival upon hypoxic, metabolic, or therapeutic stresses) in the context of specific breast cancer molecular portraits. We now recognize that the striking heterogeneity of breast cancer in terms of tumor histology, clinical presentation, and response to therapy can be captured on a molecular level by gene-expression profiling, which has revealed that each breast tumor has its own unique molecular portrait (Perou et al., 2000; Sørlie et al., 2001, 2003; Sotiriou et al., 2003). Genomic studies have established and confirmed five major breast-cancer
TL;DR: The multifaceted and redundant mechanisms through which metformin-reprogrammed energy metabolism at both the organismal and the cellular level may constitute a novel and valuable strategy to prevent and treat breast cancer disease are reviewed.