Publication:
Targeting the androgen receptor in breast cancer
Targeting the androgen receptor in breast cancer
dc.contributor.advisor | Lim, Elgene | en_US |
dc.contributor.advisor | Tilley, Wayne | en_US |
dc.contributor.advisor | Hickey, Theresa | en_US |
dc.contributor.author | Chia, Kee Ming | en_US |
dc.date.accessioned | 2022-03-15T12:23:01Z | |
dc.date.available | 2022-03-15T12:23:01Z | |
dc.date.issued | 2018 | en_US |
dc.description.abstract | Estrogen receptor positive (ER+) breast cancer constitutes 70% of all breast cancers and anti-ER therapies such as aromatase inhibitors and tamoxifen represent the main therapeutic strategies in the treatment of this disease. Unfortunately, up to 30% of all primary ER+ tumours will ultimately develop endocrine-resistance and progress on ER-targeted therapies resulting in disease-related morbidity. As a result, there is an urgent medical need for novel therapeutic strategies capable of managing endocrine-resistant breast cancer. Androgen receptor (AR) is expressed in up to 90% of ER+ breast cancers. AR functions as a tumour suppressor in primary ER+ breast cancer and high AR positivity is strongly associated with a favourable patient outcome in the ER+ setting. However, the role of AR in endocrine-resistant breast tumours is highly controversial with data supporting both oncogenic and tumour suppressive functions reported in the literature. Here I have used different modulatory approaches on in vitro and in vivo preclinical models to dissect the functions of AR and determine the best approach to target AR in endocrine-resistant breast cancer. I use an siRNA-mediated approach to knock down AR in cell line models and discover that the basal expression of AR contributes to endocrine-resistance and that loss of AR restores classical ER signalling and reverses endocrine-resistance. However, inhibiting the transcriptional activity of AR with enzalutamide does not recapitulate this effect, suggesting that it is the non-canonical activity of AR which contributes to endocrine-resistance. In contrast, I show that activation of AR by either 5-α dihydrotestosterone (DHT) or selective AR modulator enobosarm in vitro and in patient derived (PDX) models of endocrine-resistance results in significant growth suppression. Mechanistically, this growth-inhibitory effect of AR activation is associated with downregulation of ER signalling. Moreover, I identify AR-regulated genes from the global gene expression of an ER+AR+ endocrine-resistant PDX model treated with DHT and establish a highly prognostic AR gene signature based on primary ER+ patients in the METABRIC dataset. This suggests that activity of AR is tumour-suppressive independent of endocrine-sensitivity. In summary, I demonstrate that activation, not antagonism, is the optimal AR-targeted therapeutic strategy in the management of endocrine-resistant breast cancer. | en_US |
dc.identifier.uri | http://hdl.handle.net/1959.4/61991 | |
dc.language | English | |
dc.language.iso | EN | en_US |
dc.publisher | UNSW, Sydney | en_US |
dc.rights | CC BY-NC-ND 3.0 | en_US |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/3.0/au/ | en_US |
dc.subject.other | Endocrine-resistance | en_US |
dc.subject.other | AR | en_US |
dc.subject.other | Breast cancer | en_US |
dc.subject.other | AR antagonist | en_US |
dc.subject.other | SARM | en_US |
dc.subject.other | DHT | en_US |
dc.title | Targeting the androgen receptor in breast cancer | en_US |
dc.type | Thesis | en_US |
dcterms.accessRights | open access | |
dcterms.rightsHolder | Chia, Kee Ming | |
dspace.entity.type | Publication | en_US |
unsw.accessRights.uri | https://purl.org/coar/access_right/c_abf2 | |
unsw.date.embargo | 2021-05-01 | en_US |
unsw.description.embargoNote | Embargoed until 2021-05-01 | |
unsw.identifier.doi | https://doi.org/10.26190/unsworks/3712 | |
unsw.relation.faculty | Medicine & Health | |
unsw.relation.originalPublicationAffiliation | Chia, Kee Ming, Garvan Institute of Medical Research, Faculty of Medicine, UNSW | en_US |
unsw.relation.originalPublicationAffiliation | Lim, Elgene, Garvan Institute of Medical Research, Faculty of Medicine, UNSW | en_US |
unsw.relation.originalPublicationAffiliation | Tilley, Wayne, University of Adelaide | en_US |
unsw.relation.originalPublicationAffiliation | Hickey, Theresa, University of Adelaide | en_US |
unsw.relation.school | Garvan Institute | * |
unsw.thesis.degreetype | PhD Doctorate | en_US |
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