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Targeting the Ezrin Adaptor Protein Sensitizes Metastatic Breast Cancer Cells to Chemotherapy and Reduces Neoadjuvant Therapy-induced Metastasis.
Hoskin, Victoria; Ghaffari, Abdi; Laight, Brian J; SenGupta, Sandip; Madarnas, Yolanda; Nicol, Christopher J B; Elliott, Bruce E; Varma, Sonal; Greer, Peter A.
Afiliação
  • Hoskin V; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
  • Ghaffari A; Division of Cancer Biology and Genetics, Queen's Cancer Research Institute; Kingston, Ontario, Canada.
  • Laight BJ; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
  • SenGupta S; Division of Cancer Biology and Genetics, Queen's Cancer Research Institute; Kingston, Ontario, Canada.
  • Madarnas Y; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
  • Nicol CJB; Division of Cancer Biology and Genetics, Queen's Cancer Research Institute; Kingston, Ontario, Canada.
  • Elliott BE; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
  • Varma S; Kingston Health Sciences Centre, Kingston, Ontario, Canada.
  • Greer PA; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
Cancer Res Commun ; 2(6): 456-470, 2022 06.
Article em En | MEDLINE | ID: mdl-36923551
The main cause of cancer-associated deaths is the spread of cancer cells to distant organs. Despite its success in the primary tumor setting, modern chemotherapeutic strategies are rendered ineffective at treating metastatic disease, largely due to the development of resistance. The adaptor protein ezrin has been shown to promote cancer metastasis in multiple preclinical models and is associated with poor prognosis in several cancer types, including breast cancer. Ezrin promotes pro-survival signaling, particularly in disseminated cancer cells, to facilitate metastatic outgrowth. However, the role of ezrin in breast cancer chemoresistance is not fully known. In this study, we show that upregulating or downregulating ezrin expression modifies the sensitivity of breast cancer cells to doxorubicin and docetaxel treatment in vitro and is associated with changes in PI3K/Akt and NFκB pathway activation. In addition, we tested the effects of systemic treatment with a small-molecule ezrin inhibitor, NSC668394, on lung metastatic burden in vivo as a monotherapy, or in combination with anthracycline- or taxane-based chemotherapy treatment. We show that anti-ezrin treatment alone reduces metastatic burden and markedly sensitizes metastases to doxorubicin or docetaxel in neoadjuvant as well as neoadjuvant plus adjuvant treatment models. Taken together, our findings demonstrate the impact of anti-ezrin treatment in modulating response to chemotherapy in breast cancer cells as well as the efficacy of anti-ezrin treatment in combination with chemotherapy at reducing metastatic burden. Significance: This work provides preclinical evidence for combining anti-ezrin treatment with chemotherapy as a novel strategy for effectively targeting metastasis, particularly in a neoadjuvant treatment setting.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama Idioma: En Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Canadá

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama Idioma: En Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Canadá