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Implementing subtype-specific pre-clinical models of breast cancer to study pre-treatment aspirin effects
Miller, I.S. Khan, S. Shiels, L.P. Das, S. O'Farrell, A.C. Connor, K. Lafferty, A. Moran, B. Isella, C.
Miller, I.S.
Khan, S.
Shiels, L.P.
Das, S.
O'Farrell, A.C.
Connor, K.
Lafferty, A.
Moran, B.
Isella, C.
Publication Date
2022-10
End of Embargo
Supervisor
Rights
© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Peer-Reviewed
Yes
Open Access status
openAccess
Accepted for publication
07/04/2022
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Department
Awarded
Embargo end date
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Additional title
Abstract
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.
Version
Published version
Citation
Miller IS, Khan S, Shiels LP et al (2022) 'Implementing subtype-specific pre-clinical models of breast cancer to study pre-treatment aspirin effects. Cancer Medicine. 11(20): 3820-3836.
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Article