Proline-rich homeodomain protein (PRH/HHEX) is a suppressor of breast tumour growth

Kershaw, Rachael M.; Roberts, Daniel; Wragg, Joseph; Shaaban, Abeer M.; Humphreys, Elizabeth; Halsall, John; Price, Louise; Bicknell, Roy; Gaston, Kevin; Jayaraman, Padma-Sheela

Abstract

Breast tumours progress from hyperplasia to ductal carcinoma in situ (DCIS) and invasive breast carcinoma (IBC). PRH/HHEX (Proline Rich Homeodomain/Haematopoietically expressed homeobox) is a transcription factor that displays both tumour suppressor and oncogenic activity in different disease contexts however, the role of PRH in breast cancer is poorly understood. Here we show that nuclear localisation of the PRH protein is decreased in DCIS and IBC compared to normal breast. Our previous work has shown that PRH phosphorylation by protein kinase CK2 prevents PRH from binding to DNA and regulating the transcription of multiple genes encoding growth factors and growth factor receptors. Here we show that transcriptionally inactive phosphorylated PRH is elevated in DCIS and IBC compared to normal breast. To determine the consequences of PRH loss of function in breast cancer cells we generated inducible PRH depletion in MCF-7 cells. We show that PRH depletion results in increased MCF-7 cell proliferation in part at least due to increased vascular endothelial growth factor signaling. Moreover we demonstrate that PRH depletion increases the formation of breast cancer cells with cancer stem cell-like properties. Finally, and in keeping with these findings, we show that PRH over-expression inhibits the growth of mammary tumours in mice. Collectively these data indicate that PRH plays a tumour suppressive role in the breast and they provide an explanation for the finding that low PRH mRNA levels are associated with a poor prognosis in breast cancer.

Citation

Kershaw, R. M., Roberts, D., Wragg, J., Shaaban, A. M., Humphreys, E., Halsall, J., …Jayaraman, P.-S. (2017). Proline-rich homeodomain protein (PRH/HHEX) is a suppressor of breast tumour growth. Oncogenesis, 6(6), Article e346. https://doi.org/10.1038/oncsis.2017.42

• Journal Article Type: Article
• Acceptance Date: Apr 20, 2017
• Online Publication Date: Jun 12, 2017
• Publication Date: Jun 12, 2017
• Deposit Date: Aug 28, 2018
• Publicly Available Date: Aug 28, 2018
• Journal: Oncogenesis
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 6
• Issue: 6
• Article Number: e346
• DOI: https://doi.org/10.1038/oncsis.2017.42
• Keywords: HHEX, PRH, breast cancer, tumour growth, cancer stem cells
• Public URL: https://nottingham-repository.worktribe.com/output/1037563
• Publisher URL: https://www.nature.com/articles/oncsis201742
• Contract Date: Aug 28, 2018