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  3. BCRP drives intrinsic chemoresistance in chemotherapy-naïve breast cancer brain metastasis

BCRP drives intrinsic chemoresistance in chemotherapy-naïve breast cancer brain metastasis

  • Sci Adv. 2023 Oct 20;9(42):eabp9530. doi: 10.1126/sciadv.abp9530.
Rebeca Uceda-Castro 1,  Andreia S Margarido 1,  Ji-Ying Song 2,  Mark C de Gooijer 3 4 5,  Hendrik A Messal 1,  Cecilia R Chambers 6 7,  Max Nobis 6 7,  Ceren H Çitirikkaya 3,  Kerstin Hahn 1,  Danielle Seinstra 8,  David Herrmann 6 7,  Paul Timpson 6 7,  Pieter Wesseling 8 9,  Olaf van Tellingen 3 10,  Claire Vennin 1,  Jacco van Rheenen 1
Affiliations

Affiliations

  • 1 Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 2 Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 3 Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 4 Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • 5 The Christie NHS Foundation Trust, Manchester, UK.
  • 6 Cancer Ecosystems Program, Garvan Institute of Medical Research, Sydney, NSW, Australia.
  • 7 School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.
  • 8 Department of Pathology, Amsterdam University Medical Centers/VUmc and Brain Tumor Center Amsterdam, Amsterdam, Netherlands.
  • 9 Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
  • 10 Mouse Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, Netherlands.
PMID: 37851804 DOI: 10.1126/sciadv.abp9530
Abstract

Although initially successful, treatments with chemotherapy often fail because of the recurrence of chemoresistant metastases. Since these tumors develop after treatment, resistance is generally thought to occur in response to chemotherapy. However, alternative mechanisms of intrinsic chemoresistance in the chemotherapy-naïve setting may exist but remain poorly understood. Here, we study drug-naïve murine breast Cancer brain metastases (BCBMs) to identify how Cancer cells growing in a secondary site can acquire intrinsic chemoresistance without cytotoxic agent exposure. We demonstrate that drug-naïve murine breast Cancer cells that form Cancer lesions in the brain undergo vascular mimicry and concomitantly express the adenosine 5'-triphosphate-binding cassette transporter breast Cancer resistance protein (BCRP), a common marker of brain endothelial cells. We reveal that expression of BCRP by the BCBM tumor cells protects them against doxorubicin and topotecan. We conclude that BCRP overexpression can cause intrinsic chemoresistance in Cancer cells growing in metastatic sites without prior chemotherapy exposure.

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