Intraductal cisplatin treatment in a BRCA-associated breast cancer mouse model attenuates tumor development but leads to systemic tumors in aged female mice

Jolien S. de Groot, Paul J. van Diest, Miranda van Amersfoort, Eva J. Vlug, Xiaojuan Pan, Natalie D. ter Hoeve, Hilde Rosing, Jos H. Beijnen, Sameh A. Youssef, Alain de Bruin, Jos Jonkers, Elsken van der Wall, Patrick W. B. Derksen*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

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    Abstract

    BRCA deficiency predisposes to the development of invasive breast cancer. In BRCA mutation carriers this risk can increase up to 80%. Currently, bilateral prophylactic mastectomy and prophylactic bilateral salpingo-oophorectomy are the only preventive, albeit radical invasive strategies to prevent breast cancer in BRCA mutation carriers. An alternative non-invasive way to prevent BRCA1-associated breast cancer may be local prophylactic treatment via the nipple.

    Using a non-invasive intraductal (ID) preclinical intervention strategy, we explored the use of combined cisplatin and poly (ADP)-ribose polymerase 1 (PARP1) inhibition to prevent the development of hereditary breast cancer. We show that ID cisplatin and PARP-inhibition can successfully ablate mammary epithelial cells, and this approach attenuated tumor onset in a mouse model of Brca1-associated breast cancer from 153 to 239 days. Long-term carcinogenicity studies in 150 syngeneic wild-type mice demonstrated that tumor incidence was increased in the ID treated mammary glands by 6.3% due to systemic exposure to cisplatin. Although this was only evident in aged mice (median age = 649 days), we conclude that ID cisplatin treatment only presents a safe and feasible local prevention option if systemic exposure to the chemotherapy used can be avoided.

    Original languageEnglish
    Pages (from-to)60750-60763
    Number of pages14
    JournalOncotarget
    Volume8
    Issue number37
    DOIs
    Publication statusPublished - 5-Sep-2017

    Keywords

    • breast cancer
    • BRCA
    • intraductal
    • cisplatin
    • olaparib
    • MAMMARY STEM-CELLS
    • HIGH FAMILIAL RISK
    • MUTATION CARRIERS
    • LONG-TERM
    • PROPHYLACTIC MASTECTOMY
    • OVARIAN-CARCINOMA
    • ESTROUS-CYCLE
    • IN-SITU
    • WOMEN
    • GLAND

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