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Project description:Purpose: Tamoxifen is the most commonly used antiestrogen drug for breast cancer treatment, however, acquired resistance is a considerable challenge in clinic. Complexity and redundancy in biological system implies tamoxifen resistance is associated with complex biological processes. The aim of this study is to attempt to reveal the mechanism of tamoxifen resistance using high-throughput sequencing technique. Methods: We applied digital gene expression (DGE), RNA-seq, Small RNA-seq, bisulifte-seq (reduced representation bisuflite sequencing (RRBS)) with Illumina sequencing platforms, and Array CGH to analyze two well-established tamoxifen resistant cell line models: one is the LCC cell line model that was derived from MCF-7 breast cancer cell line and developed tamoxifen resistance following a step-wise strategy. This cell line model includes LCC0 (estrogen-dependent and tamoxifen sensitive), LCC1 (estrogen-independent and tamoxifen sensitive), LCC2 (derived from LCC1 with increased small-dosage tamoxifen treatment, estrogen-independent, and tamoxifen-resistant), and LCC9 (derived from LCC1 with increased small-dosage fluvestrant treatment, estrogen-independent, and cross-resistance to both fluvestrant and tamoxifen). The other is the TAMR cell line model that was derived from MCF-7 breast cancer cell line and developed four tamoxifen-resistant sublines following the strategy of high-dosage of tamoxifen treatment. Each subline was developed from the survived single cell after the tamoxifen treatment. Results: The DGE and RNA-seq results showed characteristic expression features for the both cell line models, for instance, high expression of SOX2 and alterations of other SOX gene family members, decreased expression of PGR, PTEN, TP53, EZH2, SMAD3, TGF-β1, DNMT1, APOBEC3B, FOXO3 and FOXO4, and increased expression of CDH1, APOBEC3H, FOXA1, TET2, TET3, TDG, MBD4, DNMT3a and DNMT3b between the tamoxifen-resistant cell lines with their matched parental cell lines. Small RNA seq showed the decreased expressions of miR-1, miR-196-3p, miR-18a-5p, miR-125b-5p, and the increased expression of miR-23a-3p, miR-26b-5p, miR-320d, miR-141-3p, miR-23a-3p, miR-30a-5p, miR-9-5p, miR-200c, miR-129-5p, miR-125b-5p, miR-1285-3p and miR-30b-5p between the tamoxifen-resistant cell lines and their matched parental cell lines. Additionally, let-7a and let-7c have been found to present high expression levels in the tamoxifen resistant cells in the both cell line models, even it showed significantly decreased in some TAMR cells compared with their parental cell line. The RRBS showed similar DNA methylation levels between the LCC cell lines. Array CGH showed a small number of copy number variants between the LCC cell lines. Conclusion: Our present study suggests the development of tamoxifen resistance is associated with a dynamic process of cell fate changing. Therefore, new therapeutic method that targets whole cell system and cell fate dynamics, will be a promising strategy.
2018-06-01 | GSE55380 | GEO
Project description:Purpose: Tamoxifen is the most commonly used antiestrogen drug for breast cancer treatment, however, acquired resistance is a considerable challenge in clinic. Complexity and redundancy in biological system implies tamoxifen resistance is associated with complex biological processes. The aim of this study is to attempt to reveal the mechanism of tamoxifen resistance using high-throughput sequencing technique. Methods: We applied digital gene expression (DGE), RNA-seq, Small RNA-seq, bisulifte-seq (reduced representation bisuflite sequencing (RRBS)) with Illumina sequencing platforms, and Array CGH to analyze two well-established tamoxifen resistant cell line models: one is the LCC cell line model that was derived from MCF-7 breast cancer cell line and developed tamoxifen resistance following a step-wise strategy. This cell line model includes LCC0 (estrogen-dependent and tamoxifen sensitive), LCC1 (estrogen-independent and tamoxifen sensitive), LCC2 (derived from LCC1 with increased small-dosage tamoxifen treatment, estrogen-independent, and tamoxifen-resistant), and LCC9 (derived from LCC1 with increased small-dosage fluvestrant treatment, estrogen-independent, and cross-resistance to both fluvestrant and tamoxifen). The other is the TAMR cell line model that was derived from MCF-7 breast cancer cell line and developed four tamoxifen-resistant sublines following the strategy of high-dosage of tamoxifen treatment. Each subline was developed from the survived single cell after the tamoxifen treatment. Results: The DGE and RNA-seq results showed characteristic expression features for the both cell line models, for instance, high expression of SOX2 and alterations of other SOX gene family members, decreased expression of PGR, PTEN, TP53, EZH2, SMAD3, TGF-β1, DNMT1, APOBEC3B, FOXO3 and FOXO4, and increased expression of CDH1, APOBEC3H, FOXA1, TET2, TET3, TDG, MBD4, DNMT3a and DNMT3b between the tamoxifen-resistant cell lines with their matched parental cell lines. Small RNA seq showed the decreased expressions of miR-1, miR-196-3p, miR-18a-5p, miR-125b-5p, and the increased expression of miR-23a-3p, miR-26b-5p, miR-320d, miR-141-3p, miR-23a-3p, miR-30a-5p, miR-9-5p, miR-200c, miR-129-5p, miR-125b-5p, miR-1285-3p and miR-30b-5p between the tamoxifen-resistant cell lines and their matched parental cell lines. Additionally, let-7a and let-7c have been found to present high expression levels in the tamoxifen resistant cells in the both cell line models, even it showed significantly decreased in some TAMR cells compared with their parental cell line. The RRBS showed similar DNA methylation levels between the LCC cell lines. Array CGH showed a small number of copy number variants between the LCC cell lines. Conclusion: Our present study suggests the development of tamoxifen resistance is associated with a dynamic process of cell fate changing. Therefore, new therapeutic method that targets whole cell system and cell fate dynamics, will be a promising strategy.
2018-06-01 | GSE55343 | GEO
Project description: Not available
| S-EPMC3974759 | biostudies-literature
Project description: Not available
| S-EPMC4530010 | biostudies-literature
Project description: Not available
| S-EPMC4449149 | biostudies-literature
Project description: Not available
| S-EPMC7253419 | biostudies-literature
Project description: Not available
| S-EPMC6555402 | biostudies-literature
Project description:Despite the availability of effective drugs that target ERα-positive breast cancer, resistance commonly occurs, resulting in relapse, metastasis, and death. Tamoxifen remains the most commonly-prescribed endocrine therapy worldwide, and “tamoxifen resistance” has been extensively studied. However, little consideration has been given to the role of tamoxifen’s primary active metabolite, endoxifen, in driving resistance mechanisms. Endoxifen is the most abundant active tamoxifen metabolite detected in patients and functions differently from the parent drug and other primary metabolites, including 4-hydroxy-tamoxifen (4HT). Many studies have shown that patients who extensively metabolize tamoxifen into endoxifen have superior outcomes relative to patients who do not, further supporting a primary role for endoxifen in driving tamoxifen responses. Therefore, “tamoxifen resistance” may be actually better modeled by “endoxifen resistance” for such patients. Here, we report the development of a novel endoxifen-resistant breast cancer cell line and have extensively compared this model to tamoxifen (4HT) and fulvestrant (ICI) resistant models. Endoxifen-resistant cells were found to be phenotypically and molecularly distinct from 4HT-resistant cells and more closely resembled ICI-resistant cells overall. Specifically, endoxifen resistance was associated with ERα and PR loss, estrogen insensitivity, EMT-like features, a unique gene signature, and striking resistance to most FDA-approved second- and third-line therapies. Given these findings, and the importance of endoxifen in the efficacy of tamoxifen therapy, our data indicate that endoxifen-resistant models may be more clinically relevant than existing models and suggest that a better understanding of endoxifen resistance could substantially improve patient care.
2021-01-11 | GSE164529 | GEO
Project description: Not available
| S-EPMC5302986 | biostudies-literature
Project description: Not available
| S-EPMC4856438 | biostudies-other