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

Haley Hieronymus, Phillip J. Iaquinta, John Wongvipat, Anuradha Gopalan, Rajmohan Murali, Ninghui Mao, Brett S. Carver and Charles L. Sawyers ()
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Haley Hieronymus: Memorial Sloan Kettering Cancer Center
Phillip J. Iaquinta: Memorial Sloan Kettering Cancer Center
John Wongvipat: Memorial Sloan Kettering Cancer Center
Anuradha Gopalan: Memorial Sloan Kettering Cancer Center
Rajmohan Murali: Memorial Sloan Kettering Cancer Center
Ninghui Mao: Memorial Sloan Kettering Cancer Center
Brett S. Carver: Memorial Sloan Kettering Cancer Center
Charles L. Sawyers: Howard Hughes Medical Institute

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01198-9

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