Abstract
While tamoxifen (TAM) is used for treating estrogen receptor (ER)a-positive breast cancer patients, its anti-breast cancer mechanisms are not completely elucidated. This study aimed to examine effects of 4-hydroxyltamoxifen (4-OH-TAM) on ER-positive (ER+) breast cancer MCF-7 cell growth and gene expression profiles. MCF-7 cell growth was inhibited by 4-OH-TAM dose-dependently with IC50 of 29 μM. 332 genes were up-regulated while 320 genes were down-regulated. The mRNA levels of up-regulated genes including STAT1, STAT2, EIF2AK2, TGM2, DDX58, PARP9, SASH1, RBL2 and USP18 as well as down-regulated genes including CCDN1, S100A9, S100A8, ANXA1 and PGR were confirmed by quantitative real-time PCR (qRT-PCR). In human breast tumor tissues, mRNA levels of EIF2Ak2, USP18, DDX58, RBL2, STAT2, PGR, S1000A9, and CCND1 were significantly higher in ER+- than in ER--breast cancer tissues. The mRNA levels of EIF2AK2, TGM2, USP18, DDX58, PARP9, STAT2, STAT1, PGR and CCND1 were all significantly higher in ER+-tumor tissues than in their corresponding tumor-adjacent tissues. These genes, except PGR and CCND1 which were down-regulated, were also up-regulated in ER+ MCF-7 cells by 4-OH-TAM. Total 14 genes mentioned above are involved in regulation of cell proliferation, apoptosis, cell cycles, and estrogen and interferon signal pathways. Bioinformatics analysis also revealed other novel and important regulatory factors that are associated with these genes and involved in the mentioned functional processes. This study has paved a foundation for elucidating TAM anti-breast cancer mechanisms in E2/ER-dependent and independent pathways.
Highlights
Breast cancer is the second most common cause of cancer-related death among women in the world [1, 2]
After MCF-7 cells were treated with 4-OH-TAM at 0 to 3.33 x 10-3 M (Table 1) for 72h, the inhibitory effects of 4-OH-TAM on MCF-7 cells were determined with CCK-8 kit
The mRNA levels of the up-regulated genes, and those of the down-regulated genes were detected by qRT-PCR and the results shown in Figure 3 indicated that the mRNA levels of Signal transducer and activator of transcription 1 (STAT1), STAT2, EIF2AK2, TGM2, DDX58, PARP9, SASH1, RBL2 and ubiquitin-like specific protease 18 (USP18) were significantly increased to 5.482, 1.806, 2.074, 4.087, 4.986, 6.840, 2.545, 2.057, and 3.806 folds, respectively, whereas those of CCDN1, S100A9, S100A8, ANXA1 and PGR were significantly reduced to 1.748, 3.924, 5.886, 2.723, and 3.443 folds, respectively, as compared to those of NC group
Summary
Breast cancer is the second most common cause of cancer-related death among women in the world [1, 2]. 246,660 new cases of invasive breast cancer, including 61,000 cases of carcinoma in situ in U.S women were estimated, among which, 40,450 patients would die in 2016 [3]. 1.7 million new cases of breast cancer occurred among women worldwide in 2012 [4]. Breast cancer is the most commonly diagnosed cancer in women in mainland China with the incident rate of 268.6/100,000 population, which has been increased by 3.9% annually [5]. Breast cancer exhibits remarkable clinical and molecular heterogeneity. Based on gene expression profiles and the status of hormone receptors, e.g. estrogen receptors alpha and beta (ERα and ERβ), progesterone receptor (PR) and overexpression of human epidermal growth factor receptor 2 (HER2), breast cancer is classified into five subtypes: i.e. luminal A(ER+ and/or PR+, HER2-, www.impactjournals.com/oncotarget
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