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Establishment and transcriptome characterization of tamoxifen-resistant canine mammary gland tumor cells
EnShuang Xu1, Tongxu Guan2, MengXin Hu2
1College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China; Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Key Laboratory of Comparative Medicine, Harbin, Heilongjiang 150030, PR China.
Abstract:
Tamoxifen (TAM) currently is still the drug of choice for endocrine therapy in patients with estrogen receptor positive breast cancer. However, the development of drug resistance not only limits the drug utilization, but also greatly reduces the survival of patients. At the same time, TAM is poorly understood in canine mammary gland tumors. Therefore, it is crucial to find effective methods to reverse drug resistance and prevent the development of drug resistance so as to improve the efficacy of endocrine therapy for breast cancer. Firstly, we successfully established two TAM-resistant canine mammary gland tumor cells lines including TAMp,TAMm by drug concentration gradient plus drug maintenance, and then we confirmed that the resistant cells have stronger proliferation, migration, invasion and cloning ability by CCK8, Wound healing assay, Transwell invasion assay and Clone formation assay. Second, we performed sequencing analysis of TAMm and CHMm and detected a large number of different expression genes, including reported and novel drug-resistant genes, and genes involved in complex biological processes. Finally, we explored the role of the classical Wnt signaling pathway in drug-resistant cells, and immunofluorescence and western blot results showed increased expression of Wnt pathway related genes β-catenin and P-GSK3β in drug-resistant cells, indicating abnormal activation of the classical Wnt/β-catenin pathway This study successfully established two TamR cell lines and assayed its resistance generation in many aspects, which provides a good experimental model and theoretical support for a more comprehensive understanding of the endocrine drug resistance mechanism.
Insights
Researchers developed tamoxifen-resistant (TAM-R) canine mammary tumor cell lines to study drug resistance mechanisms. These cells exhibit enhanced growth and invasion, with abnormal Wnt/β-catenin pathway activation, offering insights into overcoming endocrine therapy resistance in breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Veterinary Medicine
Background:
- Tamoxifen (TAM) is a primary endocrine therapy for estrogen receptor-positive breast cancer, but drug resistance limits its effectiveness.
- Understanding TAM resistance is crucial for improving treatment outcomes and is poorly understood in canine mammary tumors.
- Developing effective strategies to overcome TAM resistance is essential for enhancing endocrine therapy efficacy.
Purpose of the Study:
- To establish tamoxifen-resistant (TAM-R) canine mammary tumor cell lines.
- To investigate the characteristics and underlying mechanisms of TAM resistance in these cells.
- To explore the role of the Wnt signaling pathway in TAM-resistant canine mammary tumors.
Main Methods:
- Established two TAM-resistant canine mammary tumor cell lines (TAMp, TAMm) using drug concentration gradients and maintenance.
- Assessed resistance by evaluating proliferation (CCK8), migration (Wound healing assay), invasion (Transwell assay), and cloning ability (Clone formation assay).
- Performed sequencing analysis and Western blot/immunofluorescence to identify differentially expressed genes and assess Wnt pathway activation (β-catenin, P-GSK3β).
Main Results:
- Successfully established TAM-R canine mammary tumor cell lines with significantly enhanced proliferation, migration, invasion, and cloning capabilities.
- Identified numerous differentially expressed genes, including known and novel drug-resistance genes, through sequencing analysis.
- Observed increased expression of β-catenin and P-GSK3β in TAM-R cells, indicating aberrant activation of the classical Wnt/β-catenin signaling pathway.
Conclusions:
- The established TAM-R cell lines serve as a valuable model for studying endocrine drug resistance mechanisms.
- Abnormal activation of the Wnt/β-catenin pathway is implicated in tamoxifen resistance in canine mammary tumors.
- This research provides a foundation for developing novel therapeutic strategies to overcome tamoxifen resistance in breast cancer.
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