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Insulin receptor substrate-1 (IRS-1) mediates progesterone receptor-driven stemness and endocrine resistance in oestrogen receptor+ breast cancer.
Dwyer, Amy R; Truong, Thu H; Kerkvliet, Carlos Perez; Paul, Kiran V; Kabos, Peter; Sartorius, Carol A; Lange, Carol A.
Afiliación
  • Dwyer AR; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Truong TH; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Kerkvliet CP; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Paul KV; Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
  • Kabos P; Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
  • Sartorius CA; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
  • Lange CA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA. lange047@umn.edu.
Br J Cancer ; 124(1): 217-227, 2021 01.
Article en En | MEDLINE | ID: mdl-33144693
BACKGROUND: Progesterone receptors (PR) are potent modifiers of endocrine responses. In aberrant signalling cancer contexts, phosphorylation events dramatically alter steroid hormone receptor action. METHODS: The transcriptomes of primary tumours and metastases in mice harbouring ER+ breast cancer patient-derived xenografts (PDXs) were analysed following single-cell RNAseq. In vitro assays were employed to delineate mechanisms of endocrine resistance and stemness. RESULTS: A 16-gene phospho-Ser294 PR (p-PR) signature predicted poor outcome in ER+ breast cancer. Relative to primary PDX tumours, metastatic lesions expressed abundant p-PR and exhibited an activated PR gene programme with elevated expression of PGR and IRS-1. Breast cancer models of activated PR lost the expression of IGF1R and acquired insulin hypersensitivity with tamoxifen insensitivity. Activated p-PR+ breast cancer cells formed increased tumourspheres with enlarged ALDH+ and CD24-/CD44 populations. E2 induced PR/IRS-1 interaction and exchange of IGF1Rß for IRS-1 in p-PR-containing transcriptional complexes. Inhibition of IRS-1 or IR and inducible IRS-1 knockdown reduced tumourspheres. Endocrine-resistant models of luminal B breast cancer induced p-PR in 3D cultures and required PR and IRS-1 for tumoursphere formation. CONCLUSIONS: Phospho-PR-B cooperates with IRS-1 to promote outgrowth of endocrine-resistant and stem-like breast cancer cells. Targeting phospho-PR/IRS-1 crosstalk may block the emergence of endocrine resistance.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Receptores de Progesterona / Resistencia a Antineoplásicos / Proteínas Sustrato del Receptor de Insulina Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Br J Cancer Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Receptores de Progesterona / Resistencia a Antineoplásicos / Proteínas Sustrato del Receptor de Insulina Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Br J Cancer Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos