Priority Research Papers:
Intraductal cisplatin treatment in a BRCA-associated breast cancer mouse model attenuates tumor development but leads to systemic tumors in aged female mice
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Jolien S. de Groot1, Paul J. van Diest1, Miranda van Amersfoort1, Eva J. Vlug1, Xiaojuan Pan1, Natalie D. ter Hoeve1, Hilde Rosing2, Jos H. Beijnen2,3, Sameh A. Youssef4, Alain de Bruin4,5, Jos Jonkers6, Elsken van der Wall7 and Patrick W.B. Derksen1
1 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
2 Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands
3 Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
4 Department of Pathobiology, Dutch Molecular Pathology Center, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
5 Department of Pediatrics, Division of Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
6 Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
7 Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
Patrick W.B. Derksen, email:
Keywords: breast cancer, BRCA, intraductal, cisplatin, olaparib
Received: February 03, 2017 Accepted: April 06, 2017 Published: June 15, 2017
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.
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