RESUMO
Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K) have been shown to transform human mammary epithelial cells (MECs). These mutations are present in all breast cancer subtypes, including basal-like breast cancer (BLBC). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 72 protein expression changes in human basal-like MECs with knock-in E545K or H1047R PIK3CA mutations versus isogenic MECs with wild-type PIK3CA. Several of these were secreted proteins, cell surface receptors or ECM interacting molecules and were required for growth of PIK3CA mutant cells as well as adjacent cells with wild-type PIK3CA. The proteins identified by MS were enriched among human BLBC cell lines and pointed to a PI3K-dependent amphiregulin/EGFR/ERK signaling axis that is activated in BLBC. Proteins induced by PIK3CA mutations correlated with EGFR signaling and reduced relapse-free survival in BLBC. Treatment with EGFR inhibitors reduced growth of PIK3CA mutant BLBC cell lines and murine mammary tumors driven by a PIK3CA mutant transgene, all together suggesting that PIK3CA mutations promote tumor growth in part by inducing protein changes that activate EGFR.
Assuntos
Neoplasias da Mama/genética , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Mutação/genética , Comunicação Parácrina , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais , Anfirregulina/metabolismo , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida , Classe I de Fosfatidilinositol 3-Quinases , Intervalo Livre de Doença , Regulação para Baixo/efeitos dos fármacos , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/antagonistas & inibidores , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Feminino , Humanos , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Comunicação Parácrina/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteômica , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas em Tandem , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: Using patient-reported and objective assessment tools, we sought to quantify cognitive symptoms and objective cognitive dysfunction in patients irradiated for skull base cancer. METHODS: Participants were assessed using the Telephone Interview for Cognitive Status (TICS) and the MD Anderson Symptom Inventory-Head and Neck module (MDASI-HN), with subsequent analysis. RESULTS: Of the 122 participants analyzed, the majority (63%) had no frank detectable cognitive impairment by TICS, with frank impairment in 6%. Overall, mean patient-reported problems with memory (MDASImemory ) was 3.3 (SD ±2.66). On recursive partition analysis, the MDASImemory cutoff point of ≥5 was associated with detectable cognitive impairment by TICS (logworth 1.69; P = .02), yet no MDASImemory threshold was associated with unambiguous absence of impairment by TICS. CONCLUSION: Approximately one third of patients had ambiguous results by TICS assessment, for whom more rigorous testing may be warranted. Moderate to severe levels of patient-reported memory complaints on the MDASI-HN module may have utility as a screening tool for cognitive dysfunction in this population.