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1.
Clin Cancer Res ; 26(6): 1432-1448, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31699826

RESUMO

PURPOSE: Despite the therapeutic success of existing HER2-targeted therapies, tumors invariably relapse. This study aimed at identifying new mechanisms responsible for HER2-targeted therapy resistance. EXPERIMENTAL DESIGN: We have used a platform of HER2-targeted therapy-resistant cell lines and primary cultures of healthy and tumor-associated fibroblasts (TAF) to identify new potential targets related to tumor escape from anti-HER2 therapies. RESULTS: We have shown that TAFs promote resistance to HER2-targeted therapies. TAFs produce and secrete high levels of FGF5, which induces FGFR2 activation in the surrounding breast cancer cells. FGFR2 transactivates HER2 via c-Src, leading to resistance to HER2-targeted therapies. In vivo, coinoculating nonresistant cell lines with TAFs results in more aggressive and resistant tumors. Resistant cells activate fibroblasts and secrete FGFR ligands, creating a positive feedback loop that fuels resistance. FGFR2 inhibition not only inhibits HER2 activation, but also induces apoptosis in cells resistant to HER2-targeted therapies. In vivo, inhibitors of FGFR2 reverse resistance and resensitize resistant cells to HER2-targeted therapies. In HER2 patients' samples, α-SMA, FGF5, and FGFR2 contribute to poor outcome and correlate with c-Src activation. Importantly, expression of FGF5 and phospho-HER2 correlated with a reduced pathologic complete response rate in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab, which highlights the significant role of TAFs/FGF5 in HER2 breast cancer progression and resistance. CONCLUSIONS: We have identified the TAF/FGF5/FGFR2/c-Src/HER2 axis as an escape pathway responsible for HER2-targeted therapy resistance in breast cancer, which can be reversed by FGFR inhibitors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Fibroblastos Associados a Câncer/patologia , Resistencia a Medicamentos Antineoplásicos , Recidiva Local de Neoplasia/tratamento farmacológico , Receptor ErbB-2/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Lapatinib/administração & dosagem , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Receptor ErbB-2/metabolismo , Transdução de Sinais , Taxa de Sobrevida , Trastuzumab/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Breast Cancer Res ; 20(1): 65, 2018 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-29973218

RESUMO

BACKGROUND: The microenvironment and stress factors like glucocorticoids have a strong influence on breast cancer progression but their role in the first stages of breast cancer and, particularly, in myoepithelial cell regulation remains unclear. Consequently, we investigated the role of glucocorticoids in ductal carcinoma in situ (DCIS) in breast cancer, focusing specially on myoepithelial cells. METHODS: To clarify the role of glucocorticoids at breast cancer onset, we evaluated the effects of cortisol and corticosterone on epithelial and myoepithelial cells using 2D and 3D in vitro and in vivo approaches and human samples. RESULTS: Glucocorticoids induce a reduction in laminin levels and favour the disruption of the basement membrane by promotion of myoepithelial cell apoptosis in vitro. In an in vivo stress murine model, increased corticosterone levels fostered the transition from DCIS to invasive ductal carcinoma (IDC) via myoepithelial cell apoptosis and disappearance of the basement membrane. RU486 is able to partially block the effects of cortisol in vitro and in vivo. We found that myoepithelial cell apoptosis is more frequent in patients with DCIS+IDC than in patients with DCIS. CONCLUSIONS: Our findings show that physiological stress, through increased glucocorticoid blood levels, promotes the transition from DCIS to IDC, particularly by inducing myoepithelial cell apoptosis. Since this would be a prerequisite for invasive features in patients with DCIS breast cancer, its clinical management could help to prevent breast cancer progression to IDC.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Ductal de Mama/sangue , Carcinoma Intraductal não Infiltrante/sangue , Glucocorticoides/sangue , Animais , Apoptose/genética , Biomarcadores Tumorais/genética , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/patologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Xenoenxertos , Humanos , Laminina/genética , Camundongos , Mioepitelioma/sangue , Mioepitelioma/genética , Mioepitelioma/patologia , Microambiente Tumoral/genética
3.
Cancer Lett ; 424: 70-83, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29548821

RESUMO

Histamine receptor 1 (HRH1) belongs to the rhodopsin-like G-protein-coupled receptor family. Its activation by histamine triggers cell proliferation, embryonic development, and tumor growth. We recently established that HRH1 is up-regulated in basal and human epidermal growth factor receptor 2 (HER2)-enriched human breast tumors and that its expression correlates with a worse prognosis. Nevertheless, the functional role of HRH1 in basal and HER2-targeted therapy-resistant breast cancer (BC) progression has not yet been addressed. Using terfenadine, a selective chemical inhibitor of HRH1, we showed that the inhibition of HRH1 activity in basal BC cells leads to sub-G0 cell accumulation, suppresses proliferation, promotes cell motility and triggers the activation of extracellular signal-regulated kinase (ERK) signaling, initiating the mitochondrial apoptotic pathway. Furthermore, HER2-targeted therapy-resistant cells express higher levels of HRH1 and are more sensitive to terfenadine treatment. Moreover, in vivo experiments showed that terfenadine therapy reduced the tumor growth of basal and trastuzumab-resistant BC cells. In conclusion, our results suggest that targeting HRH1 is a promising new clinical approach to consider that could enhance the effectiveness of current therapeutic treatment in patients with basal and BC tumors resistant to HER2-targeted therapies.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Terfenadina/administração & dosagem , Trastuzumab/administração & dosagem , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacologia , Humanos , Células MCF-7 , Camundongos , Neoplasia de Células Basais/tratamento farmacológico , Neoplasia de Células Basais/metabolismo , Receptor ErbB-2/metabolismo , Terfenadina/farmacologia , Trastuzumab/farmacologia , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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