Brca1-deficient murine mammary epithelial cells have increased sensitivity to CDDP and MMS.
In this report we describe the isolation of an isogenic pair of Brca1(++) and Brca1(-/-) murine mammary epithelial cells (MMECs). These cells were isolated from Brca1 conditional knock out mice which contained loxP sites flanking exon 11 of the Brca1 gene (Brca1(fl/f1)) and then immortalized by infection with HPV-16E6 retrovirus to degrade p53 protein. Brca1(-/-) MMECs were generated by deletion of exon 11 following transduction of Brca1(fl/f1) MMECs with a retroviral vector expressing Cre recombinase. Brca1-deficiency rendered MMECs sensitive to cis-platinum (II) diamine dichloride (CDDP) and methylmethane sulfonate (MMS). The Brca1(+/+) and Brca1(-/-) MMECS is the only known pair of isogenic mammary epithelial cell lines. The understanding of the mechanisms of the CDDP sensitivity of the BRCA1-deficient mammary epithelial cells would be very important in understanding how BRCA1-deficiency plays out in tissue specific breast cancer chemotherapy. These studies support the role of BRCA1 in the CDDP-induced and MMS-induced DNA damage and repair by p53-independent pathways.
Sgagias
Magdalene K
MK
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA. msgagias@unmc.edu
Wagner
Kay-Uwe
KU
Hamik
Brad
B
Stoeger
Scott
S
Spieker
Rebecca
R
Huber
L Julie
LJ
Chodosh
Lewis A
LA
Cowan
Kenneth H
KH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle; D002461:Cell Line, Transformed; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D020128:Inhibitory Concentration 50; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects; D008741:Methyl Methanesulfonate / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D013997:Time Factors
D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D009944:Organoplatinum Compounds; D008741:Methyl Methanesulfonate