Abstract
Fanconi anemia complementation group-F (FANCF) is a key factor to maintain the function of FA/BRCA, a DNA-damage response pathway. However, the functional role of FANCF in breast cancer has not been elucidated. In this study, we examined the effects and mechanisms of FANCF-RNAi on the sensitivity of breast cancer cells to mitoxantrone (MX). FANCF silencing by FANCF-shRNA blocked functions of FA/BRCA pathway through inhibition of FANCD2 mono-ubiquitination in breast cancer cell lines MCF-7 and T-47D. In addition, FANCF shRNA inhibited cell proliferation, induced apoptosis, and chromosome fragmentation in both breast cancer cells. We also found that FANCF silencing potentiated the sensitivity to MX in breast cancer cells, accompanying with an increase in intracellular MX accumulation and a decrease in BCRP expression. Furthermore, we found that the blockade of FA/BRCA pathway by FANCF-RNAi activated p38 and JNK MAPK signal pathways in response to MX treatment. BCRP expression was restored by p38 inhibitor SB203580, but not by JNK inhibitor SP600125. FANCF silencing increased JNK and p38 mediated activation of p53 in MX-treated breast cancer cells, activated the mitochondrial apoptosis pathway. Our findings indicate that FANCF shRNA potentiates the sensitivity of breast cancer cells to MX, suggesting that FANCF may be a potential target for therapeutic strategies for the treatment of breast tumors.
Highlights
Fanconi anemia (FA) is a rare chromosome instability syndrome that is characterized by bone marrow failure, developmental abnormalities, and a high risk for the development of cancers, such as hematological malignancies, solid tumors of the head and neck region, and gynecological tumors [1,2,3]
We found that expression of Fanconi anemia complementation group-F (FANCF) in the two cell lines (MCF-7 and T-47D) was inhibited in a time-dependent manner, as compared with the control (Fig. 1A and Fig. 1B)
These results suggested that inactivation of the FA/breast cancer susceptibility gene (BRCA) signaling pathway was induced by gene silencing of FANCF in breast cancer cells
Summary
Fanconi anemia (FA) is a rare chromosome instability syndrome that is characterized by bone marrow failure, developmental abnormalities, and a high risk for the development of cancers, such as hematological malignancies, solid tumors of the head and neck region, and gynecological tumors [1,2,3]. FANC proteins are involved in cell cycle regulation, DNA damage and repair, apoptosis, gene transcription, and maintenance of genomic integrity through common FA/ breast cancer susceptibility gene (BRCA) cellular pathways [10]. As an adaptor protein of the FANC group, FANCF stabilizes component of FA core complex, and maintains the biological functions of the FA/BRCA pathway by interacting with the FANCC/FANCE subunit through its N-terminal, and with the FANCA/FANCG subunit through its C-terminal [11]. Low expression of FANCF is known to lead to FANCD2 ubiquitin inactivation and dysfunction of the FA/BRCA pathway, which promote the sensitivity of tumor cells to DNA cross-linking agents, such as melphalan, cisplatin, and mitomyclin C in gliomas, myelomas, and ovarian cancers[18,19,20,21]. The effect of low expression of FANCF on sensitivity of breast cancer to drugs remains unclear
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