Enhanced sensitivity to cisplatin and gemcitabine in Brca1-deficient murine mammary epithelial cells

Abstract

BackgroundBreast cancers due to germline mutations or altered expression of the BRCA1 gene associate with an aggressive clinical course and frequently exhibit a "triple-negative" phenotype, i.e. lack of expression of the estrogen and progesterone hormone receptors and lack of overexpression of the HER2/NEU oncogene, thereby rendering them relatively insensitive to hormonal manipulation and targeted HER2 therapy, respectively. BRCA1 plays a role in multiple DNA repair pathways, and thus, when mutated, results in sensitivity to certain DNA damaging drugs.ResultsHere, we used a Brca1 murine mammary epithelial cell (MMEC) model to examine the effect of loss of Brca1 on cellular sensitivity to various chemotherapy drugs. To explore novel therapeutic strategies, we included DNA damaging and non-DNA damaging drugs whose mechanisms are dependent and independent of DNA repair, respectively, and drugs that are used in standard and non-standard lines of therapy for breast cancer. To understand the cellular mechanism, we also determined the role that DNA repair plays in sensitivity to these drugs. We found that cisplatin and gemcitabine had the greatest specific therapeutic benefit to Brca1-deficient MMECs, and that when used in combination produced a synergistic effect. This sensitivity may be attributed in part to defective NER, which is one of the DNA repair pathways normally responsible for repairing DNA adducts produced by cisplatin and is shown in this study to be defective in Brca1-deficient MMECs. Brca1-deficient MMECs were not differentially sensitive to the standard breast cancer chemotherapy drugs doxorubicin, docetaxel or 5-FU.ConclusionsBoth cisplatin and gemcitabine should be explored in clinical trials for first line regimens for BRCA1-associated and triple-negative breast cancer.

BRCA/Fanconi anemia pathway implicates chemoresistance to gemcitabine in biliary tract cancer

“…Two mechanisms are known for the repair of DNA double strand breaks: HRR and non‐homologous end joining. The former involves the BRCA/FA pathway and specifically repairs “fatal DNA double strand breaks.” As BRCA‐silenced cells were reported to be sensitized to not only CDDP, but also GEM, the BRCA/FA pathway would be necessary for the DDR after GEM or CDDP exposure, and this was supported by our results of silencing BRCA2 , FANCD2 and RAD51c . In contrast, short‐term and long‐term exposure to GEM induced temporal and/or sustained elevated expression of BRCA/FA pathway genes, which could induce co‐resistance against CDDP as in previous reports of lung cancer and pancreatic cancer .…”

Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice

“…Several mechanisms have been implicated in mediating gemcitabine resistance, including loss of membrane import transporters, downregulation of dCK, increased formation of inactive metabolites (dFdU), upregulation of RNR or downstream inhibition of caspase executioners that control apoptosis signaling (51, 52). Interestingly, DNA repair is not associated with cellular response to gemcitabine-DNA adducts (53), even though the in vitro cytotoxicity directly correlates with the level of drug incorporation into DNA (50, 54). Analysis of three genes commonly found to be implicated in resistance toward gemcitabine based chemotherapy (RRM1, RRM2 and hENT1) showed no correlation between expression level and PDX tumor response toward chemotherapy (Figure 3, SI Figures 3 and 4).…”

In Vitro Enhanced Sensitivity to Cisplatin in D67Y BRCA1 RING Domain Protein

“…This contributes to the inhibition of nuclear DNA repair and transcription function. Therefore, the increased cisplatin sensitivity in the BRCA1-mutated breast cancers might be related to an impaired BRCA1 function normally responsible for repairing DNA adducts produced by cisplatin, and ultimately results in cell death 26–28. It suggests that the BRCA1 gene product acts as a key modulator of drug sensitivity in breast cancer cells 29.…”