Poster Presentation 35th Lorne Cancer Conference 2023

Beta blockade enhances anthracycline control of metastasis in triple negative breast cancer  (#119)

Aeson Chang 1 , Edoardo Botteri 2 , Sasagu Kurozumi 3 , Steven W Cole 4 , Gavin W Lambert 5 , Erica K Sloan 1
  1. Monash Institute of Pharmaceutical Sciences, Parkville, VICTORIA, Australia
  2. Department of Research, Cancer Registry of Norway, Oslo, Norway
  3. Department of Breast Surgery, International University of Health and Welfare, Chiba, Japan
  4. Departments of Psychiatry & Biobehavioral Sciences and Medicine, University of California Los Angeles, California, USA
  5. Iverson Health Innovation Research Institute and School of Health Sciences, Swinburne University of Technology, Melbourne, Australia

Beta-adrenergic blockade has been associated with improved cancer survival in triple negative breast cancer (TNBC) patients, but the mechanisms of these effects remain unclear. In clinical epidemiological analyses we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence and mortality. We recapitulated these effects in xenograft mouse models of TNBC and found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity in tumours via the induction of nerve growth factor (NGF) by tumour cells. Neurotoxin inhibition of sympathetic neural signalling, genetic deletion of NGF, and pharmacologic blockade of  b2-adrenoceptor, all significantly enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis. These findings reveal an unanticipated neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact and can be overcome by inhibiting  b2-adrenergic signalling in the tumour microenvironment. Supplementing anthracycline chemotherapy with adjunctive  b2-adrenergic antagonists represents a novel therapeutic strategy for enhancing the clinical management of TNBC.