ABSTRACT
Breast cancer treatment with poly(ADPribose)polymerase (PARP) inhibitors is currently limited to cells defective in the homologous recombination repair (HRR) pathway. The chemical inhibition of many HRR deficiency genes may sensitize cancer cells to PARP inhibitors. In the present study, Rad51, a central player in the HRR pathway, was selected to explore additional low variation and highly representative markers for PARP inhibitor activity. A CRISPR/Cas9based saturated mutation approach for the Rad51 WALKER domain was used to evaluate the sensitivity of the PARP inhibitor olaparib. Five amino acid mutation sites were identified in olaparibresistant cells. Two Rad51 haplotypes were assembled from the mutations, and may represent useful pharmacogenomic markers of PARP inhibitor sensitivity.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Rad51 Recombinase , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , CRISPR-Cas Systems/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Female , Haplotypes , Humans , Mutagenesis , Phthalazines/pharmacology , Phthalazines/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Rad51 Recombinase/genetics , Rad51 Recombinase/metabolismABSTRACT
The factor that binds to the inducer of short transcripts-1 (FBI-1) is a transcription suppressor and an important proto-oncogene that plays multiple roles in carcinogenesis and therapeutic resistance. In the present work, our results indicated that FBI-1 enhanced the resistance of triple-negative breast cancer (TNBC) cells to chemotherapeutic agents by repressing the expression of micoRNA-30c targeting the pregnane X receptor (PXR). The expression of FBI-1 was positively related to PXR and its downstream drug resistance-related genes in TNBC tissues. FBI-1 enhanced the expression of PXR and enhanced the activation of the PXR pathway. The miR-30c decreased the expression of PXR by targeting the 3'-UTR of PXR, and FBI-1 increased the expression of PXR by repressing miR-30c's expression. Through the miR-30c/PXR axis, FBI-1 accelerated the clearance or elimination of antitumor agents in TNBC cells (the TNBC cell lines or the patients derived cells [PDCs]) and induced the resistance of cells to antitumor agents. Therefore, the results indicated that the miR-30c/PXR axis participates in the FBI-1-mediated drug-resistance of TNBC cells.