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. sawyersc@mskcc.org.

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.

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