Abstract
Tamoxifen (TAM) resistance is an important clinical problem in the treatment of breast cancer. In order to identify the mechanism of TAM resistance for estrogen receptor (ER)-positive breast cancer, we screened the transcriptome using RNA-seq and compared the gene expression profiles between the MCF-7 mamma carcinoma cell line and the TAM-resistant cell line TAMR/MCF-7, 52 significant differential expression genes (DEGs) were identified including SLIT2, ROBO, LHX, KLF, VEGFC, BAMBI, LAMA1, FLT4, PNMT, DHRS2, MAOA and ALDH. The DEGs were annotated in the GO, COG and KEGG databases. Annotation of the function of the DEGs in the KEGG database revealed the top three pathways enriched with the most DEGs, including pathways in cancer, the PI3K-AKT pathway, and focal adhesion. Then we compared the gene expression profiles between the Clinical progressive disease (PD) and the complete response (CR) from the cancer genome altas (TCGA). 10 common DEGs were identified through combining the clinical and cellular analysis results. Protein-protein interaction network was applied to analyze the association of ER signal pathway with the 10 DEGs. 3 significant genes (GFRA3, NPY1R and PTPRN2) were closely related to ER related pathway. These significant DEGs regulated many biological activities such as cell proliferation and survival, motility and migration, and tumor cell invasion. The interactions between these DEGs and drug resistance phenomenon need to be further elucidated at a functional level in further studies. Based on our findings, we believed that these DEGs could be therapeutic targets, which can be explored to develop new treatment options.
Highlights
Public health data indicate that breast cancer is the most frequent and the second leading cause of death due to malignant diseases among women in the world
In order to identify the mechanism of TAM resistance for estrogen receptor (ER)-positive breast cancer, we screened the transcriptome using RNA-seq and compared the gene expression profiles between the MCF-7 mamma carcinoma cell line and the TAM-resistant cell line TAMR/MCF-7, 52 significant differential expression genes (DEGs) were identified including SLIT2, ROBO, LHX, KLF, VEGFC, BAMBI, LAMA1, FLT4, PNMT, DHRS2, MAOA and ALDH
We showed that DHRS2 was down-regulated in the TAMR/MCF-7 cells, which suggests that decreased expression of DHRS2 is associate with tumor progression, wherein it acts by inhibiting p53 protein expression
Summary
Public health data indicate that breast cancer is the most frequent and the second leading cause of death due to malignant diseases among women in the world. As a selective estrogen-receptor modulator (SERM), TAM is approved by the Food and Drug Administration (FDA) to treat both early and advanced ER-positive breast cancer in pre- and post-menopausal women, and recommended for 10 years to reduce the incidence of breast cancer [2]. Endocrine www.impactjournals.com/oncotarget therapy resistance is closely associated with ER related pathways in ER-positive breast cancer, including loss of ER expression, posttranslational modifications of ER, increased AP1 activity, deregulation of ER co-activators, and deregulation of the cell cycle [3,4,5,6,7]. Emerging evidence suggests that TAM resistance can be caused by increased receptor tyrosine kinase signaling, which leading to the activation of the Erk and PI3K pathways. Preclinical studies had shown that breast cancer cells with activated PI3K/Akt/mTOR signaling are resistant to antiestrogen therapy [8]. Our purpose of this study was to identify the DEGs related to acquired TAM resistance using clinical and cellular RNA-seq data
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