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

• Published in: EBioMedicine 2016-11, Vol.13 (C), p.132-145
• Main Authors: Nogués, Laura, Reglero, Clara, Rivas, Verónica, Salcedo, Alicia, Lafarga, Vanesa, Neves, Maria, Ramos, Paula, Mendiola, Marta, Berjón, Alberto, Stamatakis, Kostas, Zhou, Xiao Zhen, Lu, Kun Ping, Hardisson, David, Mayor, Federico, Penela, Petronila
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Apoptosis - genetics; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Breast transformation; Cancer; Cell Line, Tumor; Cell Proliferation; Cell Survival - genetics; Cell Transformation, Neoplastic - metabolism; Disease Models, Animal; Female; G-Protein-Coupled Receptor Kinase 2 - genetics; G-Protein-Coupled Receptor Kinase 2 - metabolism; Gene Expression; GRK2; HDAC6; Histone Deacetylase 6; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Mice, Transgenic; Models, Biological; NIMA-Interacting Peptidylprolyl Isomerase - metabolism; Pin1; Prognosis; Research Paper; RNA Interference; RNA, Small Interfering - genetics; Signal Transduction; Tumor Burden
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2016.09.030

In addition to oncogenic drivers, signaling nodes can critically modulate cancer-related cellular networks to strength tumor hallmarks. We identify G-protein-coupled receptor kinase 2 (GRK2) as a relevant player in breast cancer. GRK2 is up-regulated in breast cancer cell lines, in spontaneous tumors in mice, and in a proportion of invasive ductal carcinoma patients. Increased GRK2 functionality promotes the phosphorylation and activation of the Histone Deacetylase 6 (HDAC6) leading to de-acetylation of the Prolyl Isomerase Pin1, a central modulator of tumor progression, thereby enhancing its stability and functional interaction with key mitotic regulators. Interestingly, a correlation between GRK2 expression and Pin1 levels and de-acetylation status is detected in breast cancer patients. Activation of the HDAC6-Pin1 axis underlies the positive effects of GRK2 on promoting growth factor signaling, cellular proliferation and anchorage-independent growth in both luminal and basal breast cancer cells. Enhanced GRK2 levels promote tumor growth in mice, whereas GRK2 down-modulation sensitizes cells to therapeutic drugs and abrogates tumor formation. Our data suggest that GRK2 acts as an important onco-modulator by strengthening the functionality of key players in breast tumorigenesis such as HDAC6 and Pin1. [Display omitted] •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.