RESUMO
Women with type 2 diabetes (T2D) have a higher risk of being diagnosed with breast cancer and have worse survival than non-diabetic women if they do develop breast cancer. However, more research is needed to elucidate the biological underpinnings of these relationships. Here, we found that forkhead box A1 (FOXA1), a forkhead family transcription factor, and metformin (1,1-dimethylbiguanide hydrochloride), a medication used to treat T2D, may impact hormone-receptor-positive (HR+) breast cancer (BC) tumor cell growth and metastasis. Indeed, fourteen diabetes-associated genes are highly expressed in only three HR+ breast cancer cell lines but not the other subtypes utilizing a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Notably, elevated FOXA1 expression correlated with poorer overall survival in patients with estrogen-receptor-positive/progesterone-receptor-positive (ER+/PR+) breast cancer. Furthermore, experiments demonstrated that loss of the FOXA1 gene inhibited tumor proliferation and invasion in vitro using MCF-7 and T47D HR+ breast cancer cell lines. Metformin, an anti-diabetic medication, significantly suppressed tumor cell growth in MCF-7 cells. Additionally, either metformin treatment or FOXA1 gene deletion enhanced tamoxifen-induced tumor growth inhibition in HR+ breast cancer cell lines within an ex vivo three-dimensional (3D) organoid model. Therefore, the diabetes-related medicine metformin and FOXA1 gene inhibition might be a new treatment for patients with HR+ breast cancer when combined with tamoxifen, an endocrine therapy.
Assuntos
Neoplasias da Mama , Proliferação de Células , Fator 3-alfa Nuclear de Hepatócito , Metformina , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Fator 3-alfa Nuclear de Hepatócito/genética , Humanos , Metformina/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Feminino , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/genética , Invasividade Neoplásica , Células MCF-7 , Receptores de Progesterona/metabolismo , Receptores de Progesterona/genéticaRESUMO
Despite overwhelming evidence of the effectiveness of secondary prevention therapies, surveys indicate poor adherence to medical treatments and lifestyle recommendations after an acute coronary syndrome. The term adherence is preferred over compliance, as the former suggests a therapeutic alliance, whereas the latter reflects passive patient obedience. Poor adherence results from a complex interplay of multiple factors at patient, practitioner and system levels. Poor adherence among patients with stable coronary artery disease is associated with increased risk of cardiovascular admissions (10%-40%), coronary interventions (10%-30%) and cardiovascular mortality (50%-80%). Improving adherence is a complex process. A range of interventions that target modifiable factors influencing adherence have been explored, but there are no guidelines to guide the choice, and multidisciplinary efforts may be needed. Future research in the area should focus on comparative efficacy of interventions to enhance adherence.
Assuntos
Síndrome Coronariana Aguda/prevenção & controle , Cooperação do Paciente , Prevenção Secundária , Aconselhamento , Comportamentos Relacionados com a Saúde , Humanos , Hipolipemiantes/administração & dosagem , Cooperação do Paciente/estatística & dados numéricos , Relações Médico-Paciente , Resultado do TratamentoRESUMO
BACKGROUND: Inducible ventricular tachycardia (VT) is a strong predictor of spontaneous ventricular tachyarrhythmia following ST-segment-elevation myocardial infarction. Reduced left ventricular ejection fraction (EF) predisposes patients to inducible VT after ST-segment-elevation myocardial infarction. However, the role of right ventricular (RV) dysfunction in predisposing to inducible VT has not been described previously. METHODS AND RESULTS: Consecutive patients with ST-segment-elevation myocardial infarction treated with primary percutaneous coronary intervention underwent predischarge radionuclide gated heart pool scan to assess ventricular EF. The study cohort included patients with reduced left ventricular EF (left ventricular EF ≤40%) who underwent electrophysiology study (n=220) in an attempt to induce VT. We defined RV dysfunction as RVEF ≤35%. The end point was sustained monomorphic VT (cycle length ≥200 ms). This was considered a positive study. No inducible arrhythmia, ventricular fibrillation, or flutter (cycle length <200 ms) was considered a negative study. Infarct region, infarct-related artery, male sex, and RVEF ≤35% were univariable predictors of positive test. After multivariable analysis, RVEF ≤35% had the strongest association as an independent predictor of inducible VT at electrophysiology study (P<0.001; odds ratio, 5.8; 95% confidence interval, 3.005-11.262). CONCLUSIONS: RV dysfunction (RVEF ≤35%) predisposed to inducible VT at electrophysiology study in patients with impaired left ventricular EF (≤40%) after acute ST-segment-elevation myocardial infarction treated with primary percutaneous coronary intervention.
