Improved relapse-free survival on aromatase inhibitors in breast cancer is associated with interaction between oestrogen receptor-α and progesterone receptor-b

Snell, C.Gough, M.Liu, C.Middleton, K.Pyke, C.Shannon, C.Woodward, N.Hickey, T.Armes, J.Tilley, W.2019-02-042019-02-042018British Journal of Cancer, 2018; 119(11):1316-13250007-09201532-1827http://hdl.handle.net/2440/117583Background: Recent pre-clinical studies indicate that activated progesterone receptor (PR) (particularly the PR-B isoform) binds to oestrogen receptor-α (ER) and reprogrammes transcription toward better breast cancer outcomes. We investigated whether ER and PR-B interactions were present in breast tumours and associated with clinical parameters including response to aromatase inhibitors. Methods: We developed a proximity ligation assay to detect ER and PR-B (ER:PR-B) interactions in formalin-fixed paraffin-embedded tissues. The assay was validated in a cell line and patient-derived breast cancer explants and applied to a cohort of 229 patients with ER-positive and HER2-negative breast cancer with axillary nodal disease. Results: Higher frequency of ER:PR-B interaction correlated with increasing patient age, lower tumour grade and mitotic index. A low frequency of ER:PR-B interaction was associated with higher risk of relapse. In multivariate analysis, ER:PR-B interaction frequency was an independent predictive factor for relapse, whereas PR expression was not. In subset analysis, low frequency of ER:PR-B interaction was predictive of relapse on adjuvant aromatase inhibitor (HR 4.831, p = 0.001), but not on tamoxifen (HR 1.043, p = 0.939). Conclusions: This study demonstrates that ER:PR-B interactions have utility in predicting patient response to adjuvant AI therapy.en© Cancer Research UK 2018 Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).Cell Line, TumorHumansBreast NeoplasmsNeoplasm Recurrence, LocalEstrogen Receptor alphaReceptors, ProgesteroneDisease-Free SurvivalImmunohistochemistryCohort StudiesAdultAgedMiddle AgedFemaleImproved relapse-free survival on aromatase inhibitors in breast cancer is associated with interaction between oestrogen receptor-α and progesterone receptor-bImproved relapse-free survival on aromatase inhibitors in breast cancer is associated with interaction between oestrogen receptor-alpha and progesterone receptor-bJournal article003010288710.1038/s41416-018-0331-30004516341000022-s2.0-85056339583448440Hickey, T. [0000-0002-2752-730X]Tilley, W. [0000-0003-1893-2626]