Invited Presentation 44th Lorne Genome Conference 2023

Invited Speaker Presentation - Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via endocrine therapy tolerance (#46)

Ghazal Sultani* 1 , Kristine Fernandez* 1 , Brian Gloss* 2 , Amy McCart Reed 3 , Sarah Alexandrou 1 , Christine Lee 1 , Ewan Millar 1 , Samantha Oakes 4 , Daniel Roden 1 , Margaret Cummings 3 , Jamie Kutasovic 3 , Leila Eshraghi 1 , Nenad Bartonicek 1 , Fatima Valdes-Mora 5 , Sunil Lakhini 3 , Peter Simpson 3 , Rob Salomon 5 , Alex Swarbrick 1 , Elgene Lim 1 , David Gallego-Ortega 6 , Paul Timpson 1 , Max Nobis 1 , Liz Caldon 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. The Westmead Institute for Medical Research, Sydney
  3. University of Queensland, Brisbane
  4. University of NSW, Sydney
  5. Children's Medical Research Institute, Sydney, NSW, Australia
  6. University of Technology, Sydney, New South Wales

Endocrine therapies are the enduring standard of care to prevent recurrence in patients with Estrogen Receptor positive (ER+) breast cancer, which accounts for ~75% of breast cancer diagnoses. However, 30% of patients treated with endocrine therapy recur, with a substantial number progressing to incurable metastatic disease. Half of recurrences are late relapses (>5 years), and while they are typically less proliferative than early recurrences, they have similar associated mortality.

Since slow proliferating metastases are prevalent in advanced ER+ drug resistant disease, we isolated a unique model of breast cancer cells that grow very slowly in the presence of endocrine therapy in vitro over >24 months, which we termed “endocrine tolerant”. These cells form small primary tumours as mammary intraductal xenografts, but readily form micro-metastases. We hypothesised that these cells are initially reprogrammed by endocrine therapy treatment, and tested this hypothesis by comparing slow growing resistant cells to cells treated for a short period with endocrine therapy using single cell RNAseq (scRNAseq). This demonstrates that unique signatures, including changes to Rac signalling, are programmed into a subset of breast cancer cells immediately following endocrine treatment, and these are maintained in an endocrine tolerant population. We validated that Rac signalling is active in situ in a biosensor mouse model of breast cancer treated with endocrine therapy. The guanine nucleotide exchange factor, P-Rex1, is upregulated as part of the Rac signature, and we establish that it is highly expressed in clinical cohorts of late recurring ER+ breast cancer by IHC and scRNAseq, and that it is predictive of late recurrence. Subsequently we demonstrate that targeting the Rac pathway via small molecule inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) is able to reduce Rac activity in vivo in endocrine therapy resistant mammary tumours, and reduce cell survival and motility in endocrine tolerant cells. Rac inhibition is thus a potential novel strategy for the treatment of late recurring ER+ breast cancers.