Dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP-32) and survival in breast cancer: a retrospective analysis of protein and mRNA expression

Kotecha, Shreeya; Lebot, Marie N.; Sukkarn, Bhudsaban; Ball, Graham; Moseley, Paul M.; Chan, Stephen Y.; Green, Andrew R.; Rakha, Emad; Ellis, Ian O.; Martin, Stewart G.; Storr, Sarah J.

Abstract

Dopamine and cAMP regulated phosphoprotein 32 kDa (DARPP-32) also known as phosphoprotein phosphatase-1 regulatory subunit 1B and encoded by the PPP1R1B gene is an inhibitor of protein phosphatase-1 and protein kinase A. DARPP-32 is expressed in a wide range of epithelial cells and some solid tumours; however, its role in breast cancer is only partially defined. DARPP-32 expression was determined using immunohistochemistry in two independent cohorts of early stage invasive breast cancer patients (discovery n = 1352; validation n = 1655), and 112 HER2 positive breast cancer patients treated with trastuzumab and adjuvant chemotherapy. PPP1R1B mRNA expression was assessed in the METABRIC cohort (n = 1980), using artificial neural network analysis to identify associated genes. In the discovery cohort, low nuclear expression of DARPP-32 was significantly associated with shorter survival (P = 0.041), which was independent of other prognostic variables (P = 0.019). In the validation cohort, low cytoplasmic and nuclear expression was significantly associated with shorter survival (both P = 0.002), with cytoplasmic expression independent of other prognostic variables (P = 0.023). Stronger associations with survival in oestrogen receptor (ER) positive disease were observed. In patients treated with trastuzumab, low nuclear expression was significantly associated with adverse progression-free survival (P = 0.031). In the METABRIC cohort, low PPP1R1B expression was associated with shortened survival of ER positive patients. Expression of CDC42 and GRB7, amongst others, were associated with PPP1R1B expression. This data suggests a role for DARPP-32 as a prognostic marker with clinical utility in breast cancer.

Citation

Kotecha, S., Lebot, M. N., Sukkarn, B., Ball, G., Moseley, P. M., Chan, S. Y., Green, A. R., Rakha, E., Ellis, I. O., Martin, S. G., & Storr, S. J. (2019). Dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP-32) and survival in breast cancer: a retrospective analysis of protein and mRNA expression. Scientific Reports, 9, 1-11. https://doi.org/10.1038/s41598-019-53529-z

• Journal Article Type: Article
• Acceptance Date: Oct 21, 2019
• Online Publication Date: Nov 18, 2019
• Publication Date: Nov 18, 2019
• Deposit Date: Jan 7, 2020
• Publicly Available Date: Jan 7, 2020
• Journal: Scientific Reports
• Electronic ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Article Number: 16987
• Pages: 1-11
• DOI: https://doi.org/10.1038/s41598-019-53529-z
• Keywords: Multidisciplinary
• Public URL: https://nottingham-repository.worktribe.com/output/3081458
• Publisher URL: https://www.nature.com/articles/s41598-019-53529-z
• Additional Information: Received: 25 March 2019; Accepted: 21 October 2019; First Online: 18 November 2019; : The authors declare no competing interests.