Abstract P4-04-13: Androstenedione initiates rapid non-genomic signalling mediated by cytoplasmic androgen receptor in aromatase inhibitor resistant breast cancer
Authors: RM Bleach, L Creevey, ADK Hill, S Madden, LS Young, SR Pennington, M McIlroy
Journal: Cancer Research (2018)

Abstract Aromatase inhibitors (AI) are the recommended first line therapy used to treat postmenopausal breast cancer. These compounds work by inhibiting the aromatase enzyme thus preventing the conversion of circulating androgens to estrogen; as a consequence they alter the tumour intracrinology and create an unopposed highly androgenic steroid environment. We have previously reported androgen receptor (AR) protein levels to be up-regulated in an AI resistant cell line (LetR cells), and subsequently identified a mechanism by which AR drives a more aggressive phenotype in AI resistant breast cancer [1]. In this current study, LetR cells are shown to be responsive to the weak androgen androstenedione (4AD), and treatment with this steroid drives an invasive phenotype in vitro. In support of this data, clinical studies have also reported increases in the serum levels of 4AD in patients that recur on AI therapy [2]. In the canonical pathway, androgens bind to the AR which results in a conformational change to an active state. Non-canonical AR activation occurs when ligand-transformed AR interacts with molecular partners within the cytosol to induce rapid intracellular signalling cascades. These events do not depend upon AR mediated gene transcription and occur extremely quickly within a manner of minutes [3]. In vitro studies using western blot analysis and co-localisation experiments have indicated 4AD treatment potentiates a resistant phenotype through non-genomic AR actions initiated by rapid second messenger signalling within the cytoplasm. Mass spectrometry (LC–MS/MS) analysis has identified androgen-mediated, rapid cytoplasmic AR protein interactions, resulting in the identification of AR partners unique to our resistant model. Of note, evaluation of AR protein and p-ERK1/2 in a cohort of primary breast cancer patients (n=363) demonstrated that high levels of cytoplasmic AR significantly diminished survival in ER+ PR- patients (p=0.023, Fisher's exact). Elevated pERK1/2 when concomitant with increased levels of cytoplasmic AR result in a significant decrease in the period of disease free survival (p=0.018). Further investigations into these AR interactors will help elucidate mechanisms of resistance to AI therapy, and in turn these novel AR protein partners will aid the identification of patients who would benefit from anti-AR therapy. References 1. Ali, A., et al., Prosaposin activates the androgen receptor and potentiates resistance to endocrine treatment in breast cancer. Breast Cancer Research : BCR, 2015. 17(1): p. 123. 2. Elliott, K.M., et al., Effects of aromatase inhibitors and body mass index on steroid hormone levels in women with early and advanced breast cancer. British Journal of Surgery, 2014. 101(8): p. 939-948. 3. Foradori, C.D., M.J. Weiser, and R.J. Handa, Non-genomic actions of androgens. Front Neuroendocrinol, 2008. 29(2): p. 169-81. Citation Format: Bleach RM, Creevey L, Hill ADK, Madden S, Young LS, Pennington SR, McIlroy M. Androstenedione initiates rapid non-genomic signalling mediated by cytoplasmic androgen receptor in aromatase inhibitor resistant breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-13.