Poster Presentation 30th Lorne Cancer Conference 2018

UNRAVELLING THE COMPLEXITY OF ANDROGEN RECEPTOR SIGNALLING IN ER+/AR+ ENDOCRINE-RESISTANT BREAST CANCER (#225)

Heloisa Helena Milioli 1 2 , Kee Ming Chia 1 2 3 , Neil Portman 1 2 , Aliza Yong 1 2 , Gerard Tarulli 4 , Rhiannon Coulson 1 2 , Wayne Tilley 4 , Theresa Hickey 4 , Elgene Lim 1 2 3
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent’s Clinical School Faculty of Medicine, Sydney, NSW, Australia
  3. University of New South Wales, Sydney, NSW, Australia
  4. Dame Roma Mitchell Cancer Research Laboratories, The University of Adelaide, Adelaide, NSW, SA

Androgen receptor (AR) is expressed in approximately 90% of estrogen receptor positive (ER+) breast cancer and is frequently retained after the development of endocrine therapy resistance. Modulators of AR have been historically recognized in the treatment of breast cancer; however, controversial proliferative and anti-proliferative effects have been reported in the resistant setting[1,2]. Emerging insights into the role of androgen signalling have revived interest in AR-targeted therapies for pre-clinical studies and imminent clinical trials[3,4]. A better understanding of the AR regulation is therefore critical to improve the rational design of trials involving AR-directed therapies.

In this study, we sought to unravel the endogenous complexity of AR downstream signalling in endocrine-resistant cell lines and patient-derived xenografts (PDX) models and further assess the efficacy of AR-targeted agents in both models. We have utilized cutting-edge technologies (ChIP-seq, RNA-seq, RIME) and applied innovative bioinformatics approaches to explore the genomic, transcriptomic and proteomic data.

Our preliminary results showed reduced cell proliferation in response to AR knockdown in cell line models suggesting a pro-survival role of AR. Gene expression profiling revealed complex changes in hallmark sets pertaining to ‘estrogen response’ and ‘PI3K-Akt signalling’ pathways. The pharmacological inhibition of AR using clinical antagonists, nonetheless, did not recapitulate these effects.

In vitro, the treatment with both DHT (AR agonist) and Enobosarm (selective AR modulator) decreased ER signalling and inhibited cell proliferation. In vivo, DHT also inhibited tumour growth of an endocrine-resistant PDX model, whereas Enzalutamide (AR antagonist) did not affect growth rates. Enobosarm, in this setting, elicited a heterogeneous response. In the DHT- and Enobosarm-treated responders, anti-tumour effects were associated with significant decreases in ER and in the proliferation marker KI-67. 

Anti-proliferative activities of AR advocate complex interactions between AR and ER in breast cancer. Further investigation of our complementary molecular data is required to elucidate AR signalling pathways and to identify predictive biomarkers for targeted therapies, placed in the appropriate context for the subsequent translation into clinical trials.

  1. McNamara KM, Moore NL, Hickey TE, Sasano H, Tilley WD. Complexities of androgen receptor signalling in breast cancer. Endocrine-related cancer. 2014 Aug 1;21(4):T161-81.
  2. Lim E, Tarulli G, Portman N, Hickey TE, Tilley WD, Palmieri C. Pushing estrogen receptor around in breast cancer. Endocrine-related cancer. 2016 Dec 1;23(12):T227-41.
  3. Lim E, Palmieri C, Tilley WD. Renewed interest in the progesterone receptor in breast cancer. Nat Commun. 2016.
  4. Chia K, O’Brien M, Brown M, Lim E. Targeting the androgen receptor in breast cancer. Current oncology reports. 2015 Feb 1;17(2):4.