Deletion of 3p13-14 locus spanning FOXP1 to SHQ1 cooperates with PTEN loss in prostate oncogenesis

  • Nat Commun. 2017 Oct 20;8(1):1081. doi: 10.1038/s41467-017-01198-9.
Haley Hieronymus  1 ,  Phillip J Iaquinta  1 ,  John Wongvipat  1 ,  Anuradha Gopalan  2 ,  Rajmohan Murali  2 ,  Ninghui Mao  1 ,  Brett S Carver  1  3 ,  Charles L Sawyers  4
Affiliations
  • 1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.
  • 2. Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.
  • 3. Department of Urology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.
  • 4. Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA. [email protected].
PMID: 29057879 DOI: 10.1038/s41467-017-01198-9
Abstract

A multigenic locus at 3p13-14, spanning FOXP1 to SHQ1, is commonly deleted in Prostate Cancer and lost broadly in a range of cancers but has unknown significance to oncogenesis or prognosis. Here, we report that FOXP1-SHQ1 deletion cooperates with PTEN loss to accelerate prostate oncogenesis and that loss of component genes correlates with prostate, breast, and head and neck Cancer recurrence. We demonstrate that Foxp1-Shq1 deletion accelerates prostate tumorigenesis in mice in combination with PTEN loss, consistent with the association of FOXP1-SHQ1 and PTEN loss observed in human cancers. Tumors with combined Foxp1-Shq1 and PTEN deletion show increased proliferation and anaplastic dedifferentiation, as well as mTORC1 hyperactivation with reduced Akt phosphorylation. Foxp1-Shq1 deletion restores expression of AR target genes repressed in Tumors with PTEN loss, circumventing PI3K-mediated repression of the androgen axis. Moreover, FOXP1-SHQ1 deletion has prognostic relevance, with Cancer recurrence associated with combined loss of PTEN and FOXP1-SHQ1 genes.