An intronic AR responsive region of <em>ZBTB16</em> but not ZBTB16 itself is critical for AR mediated tumour suppression in ER positive breast cancer — ASN Events
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  2. Poster Session 2
  3. An intronic AR responsive region of ZBTB16 but not ZBTB16 itself is critical for AR mediated tumour suppression in ER positive breast cancer

An intronic AR responsive region of ZBTB16 but not ZBTB16 itself is critical for AR mediated tumour suppression in ER positive breast cancer (#271)

Maliha Wajahat 1 , Anzu Okada 2 , Zeyad Nassar 2 , Wayne Tilley 1 , Theresa Hickey 1 , Amy Dwyer 1
  1. Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, Faculty of Health and Medical Sciences, , University of Adelaide, Adelaide, SA, Australia
  2. South Australian Health and Medical Research Institute, South Australian immunoGENomics Cancer Institute (SAiGENCI), University of Adelaide, Adelaide, Australia, Adelaide, SA, Australia

Extensive genomic profiling has established that the androgen receptor (AR) activation reprograms transcription and suppresses growth of estrogen receptor-positive (ER+) breast cancers1-2, yet the precise enhancer elements that direct these tumour-suppressive effects remain undefined. Here, we show that a conserved intronic enhancer within ZBTB16, rather than the gene’s coding function, is necessary for AR-mediated growth suppression in ER+ breast cancer models. Modulating ZBTB16 expression alone does not alter ER+ breast cancer cell proliferation nor the ability of AR to suppress estradiol (E2)-stimulated proliferation. In contrast, CRISPR/Cas9 deletion of the intron 3 hormone response region (HRR) abolishes AR-dependent induction of ZBTB16 and negates AR-mediated inhibition of E2-stimulated growth, while leaving progesterone receptor (PR)-mediated growth suppression intact. Transcriptomic analysis revealed that HRR loss reshaped the AR-mediated transcriptome, repressing induction of canonical AR targets and transcriptional programs normally integrated into an epithelial differentiation network. High expression of HRR-regulated genes was associated with significantly improved overall and relapse-free survival in ER+ breast cancer patients from the METABRIC cohort, independent of clinical covariates. Finally, chromatin interaction analysis suggested that the HRR engages in looping interactions with a distal intergenic enhancer, nominating this site as a potential structural hub for AR-dependent enhancer-promoter communication. Together, these findings establish the ZBTB16 intron 3 enhancer as critical for AR tumour-suppressive activity in ER+ breast cancer and highlight enhancer selectivity as a key determinant of steroid receptor genomic function.

  1. 1. Hickey, T.E. et al. The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer. Nat Med 27, 310-320 (2021).
  2. 2. Palmieri, C. et al. Activity and safety of enobosarm, a novel, oral, selective androgen receptor modulator, in androgen receptor-positive, oestrogen receptor-positive, and HER2-negative advanced breast cancer (Study G200802): a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial. The Lancet Oncology 25, 317-325 (2024).