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Next Generation Sequencing Facilitates Quantitative Analysis of human breast cancer cell T47D and T47D-TR Transcriptomes

ABSTRACT: To gain new insight into the resistance to hormonal therapy in breast cancer, we generated a tamoxifen-resistant human breast cancer cell line T47D-TR by exposing estrogen-sensitive cell line T47D to increasing concentrations of 4-hydroxy tamoxifen (4-OHT) and identified its resistance with different ways. What we interested is the underlying mechanisms of breast cancer tamoxifen resistance which was not reported yet.Here, we detect the RNA sequence of both the two cell lines hoping to find some evidence.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125738 | GEO | 2020/01/28

REPOSITORIES: GEO

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Project description:Background: Up to 40% of patients with estrogen receptor positive (ER+) breast cancer experience treatment resistance and disease recurrence, often caused by the upregulation of growth factor receptors. Understanding the mechanisms of resistance, and the identification of novel therapeutic targets is, therefore, of vital importance if breast cancer prognosis is to be further improved. Fibroblast growth factor receptor 1 (FGFR1) is a potential driver of endocrine resistance; however, clinically successful attempts at targeting FGFR1 activity in breast cancer are rare and may result from an inability to correctly identify patients that could benefit from such treatment. The identification of additional genes associated with an FGFR1-mediated mechanism of resistance will provide a more precise classification scheme for FGFR1-dependency in breast cancer. Methods: Live cell imaging and RNA sequencing of ER+ breast cancer cell lines (CAMA1, T47D, tamoxifen resistant T47D) were used to investigate FGFR1-dependency in breast cancer, mechanisms of endocrine resistance and the effects of treatment with tamoxifen and erdafitinib. An FGFR1-amplified ER+ breast cancer patient-derived xenograft (PDX) model was used to assess the effects of targeting FGFR1 in vivo. Gene expression analysis of human breast cancer from The Cancer Genome Atlas (TCGA) was used for clinical validation. Results: We evaluated the effects of targeting FGFR1 in ER+/HER2- breast cancer with aberrant FGFR1 amplification and/or overexpression. We found that the FGFR tyrosine kinase inhibitor (TKI) erdafitinib inhibited cell proliferation of FGFR1-amplified CAMA1 cells in vitro. Additionally, erdafitinib significantly enhanced the anti-proliferative effect of 4-hydroxytamoxifen (4-OHT) and its anti-tumor effect was also demonstrated in vivo. Further, we demonstrated that the proliferation of FGFR1-overexpressing tamoxifen-resistant T47D (TR-T47D) cells is dependent on FGFR1 activity. Moreover, these TR-T47D cells are re-sensitized to tamoxifen upon treatment with erdafitinib. Finally, we found that upregulation of genes related to epithelial-mesenchymal-transition (EMT) correlates with FGFR1 overexpression, and is reversed by FGFR inhibition. Conclusions: In this study we demonstrated that targeting FGFR1 in ER+/HER2- breast cancer with aberrant FGFR1 activity has the potential to inhibit tumor growth and to re-sensitize resistant tumors to tamoxifen. Furthermore, we identified a functional relationship between EMT, FGFR activity and endocrine resistance in breast tumorigenesis.

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Next Generation Sequencing Facilitates Quantitative Analysis of human breast cancer cell T47D and T47D-TR Transcriptomes

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