Implementing subtype-specific pre-clinical models of breast cancer to study pre-treatment aspirin effects.pdf (2.21 MB)
Download file

Implementing subtype-specific pre-clinical models of breast cancer to study pre-treatment aspirin effects

Download (2.21 MB)
journal contribution
posted on 09.06.2022, 16:19 by Ian MillerIan Miller, Sonja Khan, Liam ShielsLiam Shiels, Sudipto DasSudipto Das, Alice C O'Farrell, Kate ConnorKate Connor, Adam Lafferty, Bruce Moran, Claudio Isella, Paul Loadman, Emer Conroy, Susan Cohrs, Roger Schibli, Robert S Kerbel, William M Gallagher, Elisabetta Marangoni, Kathleen BennettKathleen Bennett, Darran O'ConnorDarran O'Connor, Róisín M Dwyer, Annette ByrneAnnette Byrne

Backgorund: Prior data suggest pre-diagnostic aspirin use impacts breast tumour biology and patient outcome. Here, we employed faithful surgical resection models of HER2+ and triple-negative breast cancer (TNBC), to study outcome and response mechanisms across breast cancer subtypes.

Method: NOD/SCID mice were implanted with HER2+ MDA-MB-231/LN/2-4/H2N, trastuzumab-resistant HER2+ HCC1954 or a TNBC patient-derived xenograft (PDX). A daily low-dose aspirin regimen commenced until primary tumours reached ~250 mm3 and subsequently resected. MDA-MB-231/LN/2-4/H2N mice were monitored for metastasis utilising imaging. To interrogate the survival benefit of pre-treatment aspirin, 3 weeks post-resection, HCC1954/TNBC animals received standard-of-care (SOC) chemotherapy for 6 weeks. Primary tumour response to aspirin was interrogated using immunohistochemistry.

Results: Aspirin delayed time to metastasis in MDA-MB-231/LN/2-4/H2N xenografts and decreased growth of HER2+ /TNBC primary tumours. Lymphangiogenic factors and lymph vessels number were decreased in HER2+ tumours. However, no survival benefit was seen in aspirin pre-treated animals (HCC1954/TNBC) that further received adjuvant SOC, compared with animals treated with SOC alone. In an effort to study mechanisms responsible for the observed reduction in lymphangiogenesis in HER2+ BC we utilised an in vitro co-culture system of HCC1954 tumour cells and mesenchymal stromal cells (MSC). Aspirin abrogated the secretion of VEGF-C in MSCs and also decreased the lymph/angiogenic potential of the MSCs and HCC1954 by tubule formation assay. Furthermore, aspirin decreased the secretion of uPA in HCC1954 cells potentially diminishing its metastatic capability.

Conclusion: Our data employing clinically relevant models demonstrate that aspirin alters breast tumour biology. However, aspirin may not represent a robust chemo-preventative agent in the HER2+ or TNBC setting.

Funding

Irish Cancer Society Collaborative Cancer Research Centre under BREAST-PREDICT grant CCRC13GAL (www.breastpredict.com)

European Union's Horizon 2020 research and innovation programme, grant agreement no. #731105 (EurOPDX Research Infrastructure, www.europdx.eu)

History

Comments

The original article is available at https://onlinelibrary.wiley.com/

Published Citation

Miller IS. Implementing subtype-specific pre-clinical models of breast cancer to study pre-treatment aspirin effects. Cancer Med. 2022;1-17

Publication Date

17 April 2022

PubMed ID

35434898

Department/Unit

  • Data Science Centre
  • Physiology and Medical Physics
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Population Health and Health Services
  • Immunity, Infection and Inflammation
  • Cancer

Publisher

Wiley

Version

  • Published Version (Version of Record)