Abstract
BackgroundBreast cancer is the most frequent malignancy in women and drug resistance is the major obstacle for its successful chemotherapy. In the present study, we analyzed the involvement of an oncofetal gene, sal-like 4 (SALL4), in the tumor proliferation and drug resistance of human breast cancer.ResultsOur study showed that SALL4 was up-regulated in the drug resistant breast cancer cell line, MCF-7/ADR, compared to the other five cell lines. We established the lentiviral system expressing short hairpin RNA to knockdown SALL4 in MCF-7/ADR cells. Down-regulation of SALL4 inhibited the proliferation of MCF-7/ADR cells and induced the G1 phase arrest in cell cycle, accompanied by an obvious reduction of the expression of cyclinD1 and CDK4. Besides, down-regulating SALL4 can re-sensitize MCF-7/ADR to doxorubicin hydrochloride (ADMh) and had potent synergy with ADMh in MCF-7/ADR cells. Depletion of SALL4 led to a decrease in IC50 for ADMh and an inhibitory effect on the ability to form colonies in MCF-7/ADR cells. With SALL4 knockdown, ADMh accumulation rate of MCF-7/ADR cells was increased, while the expression of BCRP and c-myc was significantly decreased. Furthermore, silencing SALL4 also suppressed the growth of the xenograft tumors and reversed their resistance to ADMh in vivo.ConclusionSALL4 knockdown inhibits the growth of the drug resistant breast cancer due to cell cycle arrest and reverses tumor chemo-resistance through down-regulating the membrane transporter, BCPR. Thus, SALL4 has potential as a novel target for the treatment of breast cancer.
Highlights
Breast cancer is the most frequent malignancy in women and drug resistance is the major obstacle for its successful chemotherapy
sal-like 4 (SALL4) is overexpressed in chemo‐resistant breast cancer cell line MCF‐7/ADR To assess the role of SALL4 in the drug resistant breast cancer cells, we detected the endogenous expression of SALL4 in the normal mammary epithelial cell line HBL-100 and five breast cancer cell lines including MCF-7, MDA-MB-231, SK-BR-3, ZR-75-1 and MCF-7/ ADR by quantitative real-time PCR (qRT-PCR) and Western blot
The relative expression level of SALL4 was significantly higher in MCF-7/ ADR cells compared with that in the other five cell lines (P < 0.05, Fig. 1a)
Summary
Breast cancer is the most frequent malignancy in women and drug resistance is the major obstacle for its successful chemotherapy. We analyzed the involvement of an oncofetal gene, sal-like 4 (SALL4), in the tumor proliferation and drug resistance of human breast cancer. Chen et al BMC Molecular Biol (2016) 17:6 causes of chemo-resistance [5,6,7,8].Interestingly, recent studies have shown that sal-like 4 (SALL4) gene, a member of the mammal homologs of Drosophila homeotic gene spalt, is shared by stem cells with tumor cells promoting their proliferation and conferring drug resistance on them. SALL4 characterizes a feature of drug resistance through the maintenance of side population cancer stem cells and affects the side population cells by regulation of ABC drug transport genes ABCG2 and ABCA3 in leukemic cells [23]. Studies on the relation between SALL4 and drug resistance and chemotherapeutic sensitivity in breast cancer are still lacking
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