RESUMO
Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor, and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor α (ERα) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG-enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents. GREB1 also ensured proper cellular reactions to different ligands by recruiting distinct sets of ERα cofactors to cis-regulatory elements, which explains the contradictory biological effects of GREB1 on breast cancer cell growth in response to estrogen or antiestrogen. In refractory cells, EZH2-dependent repression of GREB1 triggered chromatin reallocation of ERα coregulators, converting the antiestrogen into an agonist. In clinical specimens from patients receiving adjuvant tamoxifen treatment, expression levels of EZH2 and GREB1 were correlated negatively, and taken together better predicted patient responses to endocrine therapy. Overall, our work suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program.Significance: This study suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program defined within. Cancer Res; 78(3); 671-84. ©2017 AACR.
Assuntos
Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigênese Genética , Receptor alfa de Estrogênio/metabolismo , Proteínas de Neoplasias/metabolismo , Tamoxifeno/farmacologia , Animais , Apoptose , Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carcinogênese , Proliferação de Células , Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Nus , Proteínas de Neoplasias/genética , Prognóstico , Regiões Promotoras Genéticas , Transcrição Gênica , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Invasive micropapillary carcinoma of the breast (IMPC) is a histological tumor variant that occurs with low frequency characterized by an inside-out formation of tumor clusters with a pseudopapillary arrangement. IMPC is an aggressive tumor with poor clinical outcome. In addition, this histological subtype usually expresses human epidermal growth factor receptor 2 (HER2) which also correlates with a more aggressive tumor. In this work we studied the clinical significance of IMPC in HER2-positive breast cancer patients treated with adjuvant trastuzumab. We also analyzed mucin 4 (MUC4) expression as a novel biomarker to identify IMPC. METHODS: We retrospectively studied 86 HER2-positive breast cancer patients treated with trastuzumab and chemotherapy in the adjuvant setting. We explored the association of the IMPC component with clinicopathological parameters at diagnosis and its prognostic value. We compared MUC4 expression in IMPC with respect to other histological breast cancer subtypes by immunohistochemistry. RESULTS: IMPC, either as a pure entity or associated with invasive ductal carcinoma (IDC), was present in 18.6% of HER2-positive cases. It was positively correlated with estrogen receptor expression and tumor size and inversely correlated with patient's age. Disease-free survival was significantly lower in patients with IMPC (hazard ratio = 2.6; 95%, confidence interval 1.1-6.1, P = 0.0340). MUC4, a glycoprotein associated with metastasis, was strongly expressed in all IMPC cases tested. IMPC appeared as the histological breast cancer subtype with the highest MUC4 expression compared to IDC, lobular and mucinous carcinoma. CONCLUSION: In HER2-positive breast cancer, the presence of IMPC should be carefully examined. As it is often not informed, because it is relatively difficult to identify or altogether overlooked, we propose MUC4 expression as a useful biomarker to highlight IMPC presence. Patients with MUC4-positive tumors with IMPC component should be more frequently monitored and/or receive additional therapies.
Assuntos
Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/mortalidade , Carcinoma Papilar/mortalidade , Mucina-4/metabolismo , Receptor ErbB-2/metabolismo , Trastuzumab/farmacologia , Adulto , Idoso , Antineoplásicos Imunológicos , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Papilar/tratamento farmacológico , Carcinoma Papilar/metabolismo , Carcinoma Papilar/patologia , Estudos de Casos e Controles , Quimioterapia Adjuvante , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/imunologia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
La quimioterapia neoadyuvante es un pilar fundamental en el tratamiento del cáncer de mama localmente avanzado, y la medida en que modifica la expresión de los receptores hormonales y her2 es motivo de controversia. esta variabilidad tiene importantes consecuencias pronósticas y terapéuticas. Objetivo: Evaluar la variabilidad de los Receptores Hormonales y del her2/neu pre y post neoadyuvancia en pacientes tratadas en el Hospital General de Agudos Carlos G. Durand. Material y método: Estudio retrospectivo de las historias clínicas de las pacientes sometidas a quimioterapia neoadyuvante entre septiembre de 2010 y septiembre de 2014. Se obtuvieron datos de 32 pacientes (34 tumores, 2 de las pacientes presentaron cáncer de mama bilateral). Se evaluaron Receptores Hormonales y her2 en la punción biopsia Core y en la pieza quirúrgica, y se analizó su concordancia. Resultados: La concordancia observada entre la biopsia pre neoadyuvancia y el tumor residual fue para re del 14,8% (k=0,60), para rp del 25,9% (k=0,33), para rh tomados en conjunto del 18,5% (k=0,35) y para her2 del 7,4% (k=0,70). Conclusiones: En nuestra serie encontramos una concordancia buena para her2, moderada para re y débil para rp y rh entre las muestras pre y post neoadyuvancia. La variabilidad encontrada justifica el retesteo de los biomarcadores en la pieza quirúrgica...
