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Functional screening reveals HORMAD1-driven gene dependencies associated with translesion synthesis and replication stress tolerance.
Tarantino, Dalia; Walker, Callum; Weekes, Daniel; Pemberton, Helen; Davidson, Kathryn; Torga, Gonzalo; Frankum, Jessica; Mendes-Pereira, Ana M; Prince, Cynthia; Ferro, Riccardo; Brough, Rachel; Pettitt, Stephen J; Lord, Christopher J; Grigoriadis, Anita; Nj Tutt, Andrew.
Afiliación
  • Tarantino D; Breast Cancer Now Research Unit, King's College London, London, UK.
  • Walker C; School of Cancer and Pharmaceutical Sciences, King's Health Partners AHSC, Faculty of Life Sciences and Medicine, King's College London, London, UK.
  • Weekes D; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
  • Pemberton H; Breast Cancer Now Research Unit, King's College London, London, UK.
  • Davidson K; School of Cancer and Pharmaceutical Sciences, King's Health Partners AHSC, Faculty of Life Sciences and Medicine, King's College London, London, UK.
  • Torga G; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
  • Frankum J; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
  • Mendes-Pereira AM; The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.
  • Prince C; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
  • Ferro R; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
  • Brough R; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
  • Pettitt SJ; The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.
  • Lord CJ; Breast Cancer Now Research Unit, King's College London, London, UK.
  • Grigoriadis A; School of Cancer and Pharmaceutical Sciences, King's Health Partners AHSC, Faculty of Life Sciences and Medicine, King's College London, London, UK.
  • Nj Tutt A; Breast Cancer Now Research Unit, King's College London, London, UK.
Oncogene ; 41(32): 3969-3977, 2022 08.
Article en En | MEDLINE | ID: mdl-35768547
HORMAD1 expression is usually restricted to germline cells, but it becomes mis-expressed in epithelial cells in ~60% of triple-negative breast cancers (TNBCs), where it is associated with elevated genomic instability (1). HORMAD1 expression in TNBC is bimodal with HORMAD1-positive TNBC representing a biologically distinct disease group. Identification of HORMAD1-driven genetic dependencies may uncover novel therapies for this disease group. To study HORMAD1-driven genetic dependencies, we generated a SUM159 cell line model with doxycycline-inducible HORMAD1 that replicated genomic instability phenotypes seen in HORMAD1-positive TNBC (1). Using small interfering RNA screens, we identified candidate genes whose depletion selectively inhibited the cellular growth of HORMAD1-expressing cells. We validated five genes (ATR, BRIP1, POLH, TDP1 and XRCC1), depletion of which led to reduced cellular growth or clonogenic survival in cells expressing HORMAD1. In addition to the translesion synthesis (TLS) polymerase POLH, we identified a HORMAD1-driven dependency upon additional TLS polymerases, namely POLK, REV1, REV3L and REV7. Our data confirms that out-of-context somatic expression of HORMAD1 can lead to genomic instability and reveals that HORMAD1 expression induces dependencies upon replication stress tolerance pathways, such as translesion synthesis. Our data also suggest that HORMAD1 expression could be a patient selection biomarker for agents targeting replication stress.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama Triple Negativas Tipo de estudio: Diagnostic_studies / Risk_factors_studies / Screening_studies Límite: Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama Triple Negativas Tipo de estudio: Diagnostic_studies / Risk_factors_studies / Screening_studies Límite: Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article Pais de publicación: Reino Unido