2. Academic Validation
  3. The Protein Encoded by the CCDC170 Breast Cancer Gene Functions to Organize the Golgi-Microtubule Network

The Protein Encoded by the CCDC170 Breast Cancer Gene Functions to Organize the Golgi-Microtubule Network

  • EBioMedicine. 2017 Aug;22:28-43. doi: 10.1016/j.ebiom.2017.06.024.
Pengtao Jiang 1,  Yueran Li 2,  Andrey Poleshko 3,  Valentina Medvedeva 4,  Natalia Baulina 5,  Yongchao Zhang 6,  Yan Zhou 7,  Carolyn M Slater 8,  Trinity Pellegrin 9,  Jason Wasserman 10,  Michael Lindy 11,  Andrey Efimov 12,  Mary Daly 13,  Richard A Katz 14,  Xiaowei Chen 15
Affiliations

Affiliations

  • 1 Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United States. Electronic address: [email protected].
  • 2 Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United States. Electronic address: [email protected].
  • 3 Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United States. Electronic address: [email protected].
  • 4 Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United States. Electronic address: [email protected].
  • 5 Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United States. Electronic address: [email protected].
  • 6 Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United States. Electronic address: [email protected].
  • 7 Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA 19111, United States. Electronic address: [email protected].
  • 8 Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United States. Electronic address: [email protected].
  • 9 Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United States. Electronic address: [email protected].
  • 10 Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United States. Electronic address: [email protected].
  • 11 Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United States. Electronic address: [email protected].
  • 12 Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United States. Electronic address: [email protected].
  • 13 Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA 19111, United States. Electronic address: [email protected].
  • 14 Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United States. Electronic address: [email protected].
  • 15 Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United States. Electronic address: [email protected].
PMID: 28687497 DOI: 10.1016/j.ebiom.2017.06.024
Abstract

Genome-Wide Association Studies (GWAS) and subsequent fine-mapping studies (>50) have implicated single nucleotide polymorphisms (SNPs) located at the CCDC170/C6ORF97-ESR1 locus (6q25.1) as being associated with the risk of breast Cancer. Surprisingly, our analysis using genome-wide differential allele-specific expression (DASE), an indicator for breast Cancer susceptibility, suggested that the genetic alterations of CCDC170, but not ESR1, account for GWAS-associated breast Cancer risk at this locus. Breast cancer-associated CCDC170 nonsense mutations and rearrangements have also been detected, with the latter being specifically implicated in driving breast Cancer. Here we report that the wild type CCDC170 protein localizes to the region of the Golgi apparatus and binds Golgi-associated microtubules (MTs), and that breast cancer-linked truncations of CCDC170 result in loss of Golgi localization. Overexpression of wild type CCDC170 triggers Golgi reorganization, and enhances Golgi-associated MT stabilization and acetyltransferase ATAT1-dependent α-tubulin acetylation. Golgi-derived MTs regulate cellular polarity and motility, and we provide evidence that dysregulation of CCDC170 affects polarized cell migration. Taken together, our findings demonstrate that CCDC170 plays an essential role in Golgi-associated MT organization and stabilization, and implicate a mechanism for how perturbations in the CCDC170 gene may contribute to the hallmark changes in cell polarity and motility seen in breast Cancer.

Keywords

CCDC170/C6ORF97; Differential allele specific expression (DASE); Genome-wide association studies (GWAS); Golgi-associated microtubules; Polarized cell migration; Tubulin acetylation.

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