Poster Presentation 35th Lorne Cancer Conference 2023

Elucidating the oncogenic role of telomere dysfunction in drug resistant ER+ breast cancer (#138)

Leila Eshraghi 1 2 , Nader Aryamanesh 3 4 , Sarah Alexandrou 1 2 , Christine Lee 1 2 , Anton Hsu 3 , Elgene Lim 1 2 , Hilda Pickett 3 4 , C. Elizabeth Caldon 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia
  3. Children’s Medical Research Institution (CMRI), Westmead, NSW, Australia
  4. School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia

Estrogen Receptor positive (ER+) breast cancer constitutes ~70% of breast cancers and is routinely treated with ER-directed/endocrine therapies (tamoxifen, aromatase inhibitors). Unfortunately, endocrine therapy resistance develops in ~30% of the patients and cancer recurs. ER+ breast cancer typically has longer telomeres and activated telomerase (hTERT), contributing to cancer cell longevity. Tamoxifen inhibits the growth of ER+ breast cancer cells and downregulates hTERT mRNA expression. We hypothesised that telomerase activity and telomere lengthening are restored in tamoxifen resistant cells and this remodelling leads to genome instability.

We first examined if telomerase expression predicts patient survival, and found that breast cancer patients with high TERT expression have poorer relapse free survival following endocrine therapy. We determined if telomere length and composition is altered upon development of endocrine therapy resistance using tamoxifen resistant (TAMR1) and passage matched control (MCF-7) breast cancer cell lines. Using QTRAP telomerase assays, we demonstrated that telomerase activity was significantly suppressed in tamoxifen treated MCF-7, 48 h and 72 h post treatment, and this corresponded to reduction in telomerase (hTERT) expression. Telomerase activity and hTERT expression was restored in resistant cell line, TAMR1. The telomeric regions of the genome were sequenced using both short read (Illumina) and long read (Oxford Nanopore Technologies; ONT) sequencing platforms, and the reads were mapped to our created telomere reference genome using Minimap2 aligner. Assessments of both WGS and ONT sequenced data revealed that telomere length decreases following tamoxifen treatment, but telomere length was restored in tamoxifen resistant cells.  This occurred primarily via an increase in the number of telomeric motif (TTAGGG).

Overall, our data indicates that telomerase reactivation and increased telomere length are important in drug resistance in ER+ breast cancer. This knowledge brings the potential to develop patients’ telomerase activation or telomeric length as a new therapeutic target for endocrine therapy resistant breast cancer.