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- Title
Implementing subtype‐specific pre‐clinical models of breast cancer to study pre‐treatment aspirin effects.
- Authors
Miller, Ian S.; Khan, Sonja; Shiels, Liam P.; Das, Sudipto; O' Farrell, Alice C.; Connor, Kate; Lafferty, Adam; Moran, Bruce; Isella, Claudio; Loadman, Paul; Conroy, Emer; Cohrs, Susan; Schibli, Roger; Kerbel, Robert S.; Gallagher, William M.; Marangoni, Elisabetta; Bennett, Kathleen; O' Connor, Darran P.; Dwyer, Róisín M.; Byrne, Annette T.
- 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.
- Subjects
ASPIRIN; HER2 positive breast cancer; ANIMAL models in research; BREAST cancer; TRIPLE-negative breast cancer; SEVERE combined immunodeficiency
- Publication
Cancer Medicine, 2022, Vol 11, Issue 20, p3820
- ISSN
2045-7634
- Publication type
Article
- DOI
10.1002/cam4.4756