G Protein-coupled Receptor Kinase 2 (GRK2) Promotes Breast Tumorigenesis Through a HDAC6-Pin1 Axis

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• 作者：Laura Nogué ; s^a ; ^b ; ^c ; Clara Reglero^a ; ^b ; Veró ; nica Rivas^a ; ^b ; Alicia Salcedo^a ; Vanesa Lafarga^a ; ^b ; ¹ ; Maria Neves^a ; Paula Ramos^a ; ^b ; Marta Mendiola^d ; Alberto Berjó ; n^e ; Kostas Stamatakis^a ; Xiao Zhen Zhou^f ; Kun Ping Lu^f ; David Hardisson^e ; Federico Mayor Jr.^a ; ^b ; ^{fmayor@cbm.csic.es} ; Petronila Penela^a ; ^b ; ^{ppenela@cbm.csic.es}
• 关键词：Breast transformation ; Cancer ; GRK2 ; HDAC6 ; Pin1 ; Acetylation
• 刊名：EBioMedicine
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：13
• 期：Complete
• 页码：132-145
• 全文大小：2802 K
• 卷排序：13

文摘

Pathways commonly altered in breast cancer converge in promoting GRK2 upregulation, leading to enhanced HDAC6 functionality. The GRK2-HDAC6 module fosters cancer hallmarks by enabling de-acetylation and gain-of function of the Prolyl Isomerase Pin1. GRK2 downregulation sensitizes cells to therapeutic drugs and abrogates tumor formation in mice.Targeting growth factors or estrogen receptors have improved the clinical outcome of certain subtypes of breast cancer, although these treatments are limited by the emergence of resistances. We uncover that G-protein-coupled receptor kinase 2(GRK2) increases in breast cancer experimental models and in certain ductal carcinoma patients, thus enhancing the transforming growth properties of both luminal and basal breast cancer cells, by augmenting the functionality of cancer-driving nodes such as Histone Deacetylase 6 and Pin1. GRK2 inhibition sensitizes breast cancer cells to chemotherapeutic agents and blocks tumor growth in mice. The GRK2-HDAC6-Pin1 axis emerges as a relevant molecular signature in breast tumorigenesis and as a potential target for combination therapies.