Your browser doesn't support javascript.
loading
CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1-ErbB-PI3K signaling.
Choi, Hee-Joo; Jin, Sora; Cho, Hani; Won, Hee-Young; An, Hee Woon; Jeong, Ga-Young; Park, Young-Un; Kim, Hyung-Yong; Park, Mi Kyung; Son, Taekwon; Min, Kyueng-Whan; Jang, Ki-Seok; Oh, Young-Ha; Lee, Jeong-Yeon; Kong, Gu.
Afiliación
  • Choi HJ; Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, Korea.
  • Jin S; Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
  • Cho H; Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
  • Won HY; Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
  • An HW; Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
  • Jeong GY; Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
  • Park YU; Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
  • Kim HY; Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
  • Park MK; Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
  • Son T; National Cancer Center, Goyang, Korea.
  • Min KW; College of Pharmacy, Seoul National University, Seoul, Korea.
  • Jang KS; Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
  • Oh YH; Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
  • Lee JY; Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
  • Kong G; Department of Medicine, College of Medicine, Hanyang University, Seoul, Korea.
EMBO Rep ; 20(10): e48058, 2019 10 04.
Article en En | MEDLINE | ID: mdl-31468695
Cyclin-dependent kinase 12 (CDK12) has emerged as an effective therapeutic target due to its ability to regulate DNA damage repair in human cancers, but little is known about the role of CDK12 in driving tumorigenesis. Here, we demonstrate that CDK12 promotes tumor initiation as a novel regulator of cancer stem cells (CSCs) and induces anti-HER2 therapy resistance in human breast cancer. High CDK12 expression caused by concurrent amplification of CDK12 and HER2 in breast cancer patients is associated with disease recurrence and poor survival. CDK12 induces self-renewal of breast CSCs and in vivo tumor-initiating ability, and also reduces susceptibility to trastuzumab. Furthermore, CDK12 kinase activity inhibition facilitates anticancer efficacy of trastuzumab in HER2+ tumors, and mice bearing trastuzumab-resistant HER2+ tumor show sensitivity to an inhibitor of CDK12. Mechanistically, the catalytic activity of CDK12 is required for the expression of genes involved in the activation of ErbB-PI3K-AKT or WNT-signaling cascades. These results suggest that CDK12 is a major oncogenic driver and an actionable target for HER2+ breast cancer to replace or augment current anti-HER2 therapies.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Transducción de Señal / Quinasas Ciclina-Dependientes / Resistencia a Antineoplásicos / Carcinogénesis / Trastuzumab Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: EMBO Rep Asunto de la revista: BIOLOGIA MOLECULAR Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Transducción de Señal / Quinasas Ciclina-Dependientes / Resistencia a Antineoplásicos / Carcinogénesis / Trastuzumab Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: EMBO Rep Asunto de la revista: BIOLOGIA MOLECULAR Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido