Abstract
Simple SummaryCancer recurrence caused by tamoxifen resistance hampers chemotherapy in breast cancer patients. The reasons behind the resistance were investigated by screening epigenetically regulated genes through analysis of methylation data from tamoxifen-resistant MCF-7 cells. MMP1 locus was found to be hypomethylated at a promoter CpG site and its expression was upregulated in the cell line, which was verified by the drug-resistant tumor tissues from breast cancer patients (n = 28). Downregulating MMP1 using a short hairpin RNA inhibited the growth of resistant cells and increased sensitivity to tamoxifen in vitro as well as in a xenografted mouse model in vivo. This study suggests that MMP1 is potentially a target gene to control tamoxifen resistance in breast cancer.Background: Tamoxifen (tam) is widely used to treat estrogen-positive breast cancer. However, cancer recurrence after chemotherapy remains a major obstacle to achieve good patient prognoses. In this study, we aimed to identify genes responsible for epigenetic regulation of tam resistance in breast cancer. Methods: Methylation microarray data were analyzed to screen highly hypomethylated genes in tam resistant (tamR) breast cancer cells. Quantitative RT-PCR, Western blot analysis, and immunohistochemical staining were used to quantify expression levels of genes in cultured cells and cancer tissues. Effects of matrix metalloproteinase-1 (MMP1) expression on cancer cell growth and drug resistance were examined through colony formation assays and flow cytometry. Xenografted mice were generated to investigate the effects of MMP1 on drug resistance in vivo. Results: MMP1 was found to be hypomethylated and overexpressed in tamR MCF-7 (MCF-7/tamR) cells and in tamR breast cancer tissues. Methylation was found to be inversely associated with MMP1 expression level in breast cancer tissues, and patients with lower MMP1 expression exhibited a better prognosis for survival. Downregulating MMP1 using shRNA induced tam sensitivity in MCF-7/tamR cells along with increased apoptosis. The xenografted MCF-7/tamR cells that stably expressed short hairpin RNA (shRNA) against MMP1 exhibited retarded tumor growth compared to that in cells expressing the control shRNA, which was further suppressed by tam. Conclusions: MMP1 can be upregulated through promoter hypomethylation in tamR breast cancer, functioning as a resistance driver gene. MMP1 can be a potential target to suppress tamR to achieve better prognoses of breast cancer patients.
Highlights
Breast cancer (BC) is one of the most common cancers in women, with over two million new cases (11.7% of all cancers) and causing the death of approximately 0.7 million patients (6.9% of all cancers) worldwide in 2020 [1]
matrix metalloproteinase-1 (MMP1) Is Upregulated by DNA Hypomethylation in tam resistant (tamR) Breast Cancer
MMP1 with a ∆β of −0.32 was selected for further investigation because it is an oncogene known to be crucial in tumor development and metastasis [33]; its epigenetic regulation and molecular mechanisms that contribute to chemo-resistance have not been elucidated
Summary
Breast cancer (BC) is one of the most common cancers in women, with over two million new cases (11.7% of all cancers) and causing the death of approximately 0.7 million patients (6.9% of all cancers) worldwide in 2020 [1]. Proliferation of cancer cells is suppressed by induction of cell death Based on these anticancer activities, tam has been widely used to treat ER+ breast cancer and has exhibited high effectiveness during the initial treatment period [7]. As observed for many other therapeutic drugs, tam-resistant (tamR) cells can emerge, which escape the drug, causing cancer recurrence [8]. Methods: Methylation microarray data were analyzed to screen highly hypomethylated genes in tam resistant (tamR) breast cancer cells. Methylation was found to be inversely associated with MMP1 expression level in breast cancer tissues, and patients with lower MMP1 expression exhibited a better prognosis for survival. Conclusions: MMP1 can be upregulated through promoter hypomethylation in tamR breast cancer, functioning as a resistance driver gene. MMP1 can be a potential target to suppress tamR to achieve better prognoses of breast cancer patients
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