BRCA1-deficient breast cancer cell lines are resistant to MEK inhibitors and show distinct sensitivities to 6-thioguanine.
Germ-line or somatic inactivation of BRCA1 is a defining feature for a portion of human breast cancers. Here we evaluated the anti-proliferative activity of 198 FDA-approved and experimental drugs against four BRCA1-mutant (HCC1937, MDA-MB-436, SUM1315MO2, and SUM149PT) and four BRCA1-wild-type (MDA-MB-231, SUM229PE, MCF10A, and MCF7) breast cancer cell lines. We found that all BRCA1-mutant cell lines were insensitive to inhibitors of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) Selumetinib and Pimasertib in contrast to BRCA1-wildtype control cell lines. However, unexpectedly, only two BRCA1-mutant cell lines, HCC1937 and MDA-MB-436, were hypersensitive to a nucleotide analogue 6-thioguanine (6-TG). SUM149PT cells readily formed radiation-induced RAD51-positive nuclear foci indicating a functional homologous recombination, which may explain their resistance to 6-TG. However, the reason underlying 6-TG resistance of SUM1315MO2 cells remains unclear. Our data reveal a remarkable heterogeneity among BRCA1-mutant cell lines and provide a reference for future studies.
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, FIN-00014, Helsinki, Finland.
Yuexi
Y
Gu
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, FIN-00014, Helsinki, Finland.
Mikko
M
Helenius
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, FIN-00014, Helsinki, Finland.|Department of Biology, University of Eastern Finland, PO Box 111, FI-80101 Joensuu, Finland.
Kristiina
K
Väänänen
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, FIN-00014, Helsinki, Finland.
Daria
D
Bulanova
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, FIN-00014, Helsinki, Finland.
Jani
J
Saarela
Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.|Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia.
Anna
A
Sokolenko
Erasmus University Medical Center, Daniel den Hoed Cancer Center, Department of Medical Oncology and Cancer Genomics Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, the Netherlands.
John
J
Martens
Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.|Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia.|Department of Oncology, I.I. Mechnikov North-Western Medical University, St.-Petersburg 191015, Russia.
Evgeny
E
Imyanitov
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, FIN-00014, Helsinki, Finland.
Sergey
S
Kuznetsov
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000235:genetics*; D001562:Benzimidazoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D061986:MCF-7 Cells; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013866:Thioguanine / Q000494:pharmacology*
C517975:AZD 6244; D000964:Antimetabolites, Antineoplastic; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D001562:Benzimidazoles; C550600:N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D013866:Thioguanine