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Updated: Jun 26, 2025
Optimization of a Multiplex RNA-based Expression Assay Using Breast Cancer Archival Material
Published on: August 1, 2018
Resf1 is a compound G4 quadruplex-associated tumor suppressor for triple negative breast cancer
Megan R Majocha1,2, Devin E Jackson1,2, Ngoc-Han Ha1
1Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Abstract:
Patients with ER-negative breast cancer have the worst prognosis of all breast cancer subtypes, often experiencing rapid recurrence or progression to metastatic disease shortly after diagnosis. Given that metastasis is the primary cause of mortality in most solid tumors, understanding metastatic biology is crucial for effective intervention. Using a mouse systems genetics approach, we previously identified 12 genes associated with metastatic susceptibility. Here, we extend those studies to identify Resf1, a poorly characterized gene, as a novel metastasis susceptibility gene in ER- breast cancer. Resf1 is a large, unstructured protein with an evolutionarily conserved intron-exon structure, but with poor amino acid conservation. CRISPR or gene trap mouse models crossed to the Polyoma Middle-T antigen genetically engineered mouse model (MMTV-PyMT) demonstrated that reduction of Resf1 resulted in a significant increase in tumor growth, a shortened overall survival time, and increased incidence and number of lung metastases, consistent with patient data. Furthermore, an analysis of matched tail and primary tissues revealed loss of the wildtype copy in tumor tissue, consistent with Resf1 being a tumor suppressor. Mechanistic analysis revealed a potential role of Resf1 in transcriptional control through association with compound G4 quadruplexes in expressed sequences, particularly those associated with ribosomal biogenesis. These results suggest that loss of Resf1 enhances tumor progression in ER- breast cancer through multiple alterations in both transcriptional and translational control.
Insights
Loss of the Resf1 gene accelerates tumor growth and metastasis in estrogen receptor-negative breast cancer, indicating its role as a tumor suppressor. This finding is crucial for understanding and potentially treating aggressive breast cancer subtypes.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Estrogen receptor-negative (ER-) breast cancer has a poor prognosis with high rates of metastasis.
- Metastasis is the leading cause of cancer mortality, necessitating research into its underlying mechanisms.
- Previous studies identified 12 genes linked to metastatic susceptibility using a mouse systems genetics approach.
Purpose of the Study:
- To identify novel genes associated with metastatic susceptibility in ER- breast cancer.
- To investigate the role of the poorly characterized gene Resf1 in ER- breast cancer progression and metastasis.
Main Methods:
- Utilized CRISPR and gene trap mouse models crossed with the MMTV-PyMT genetically engineered mouse model.
- Assessed tumor growth, overall survival, and incidence/number of lung metastases upon reduction of Resf1.
- Analyzed matched tail and primary tumor tissues to investigate Resf1's potential tumor suppressor function.
- Performed mechanistic analysis to explore Resf1's role in transcriptional control and G4 quadruplex interactions.
Main Results:
- Reduction of Resf1 significantly increased tumor growth and decreased overall survival in MMTV-PyMT mice.
- Loss of Resf1 led to a higher incidence and greater number of lung metastases.
- Analysis revealed loss of the wildtype Resf1 copy in tumor tissue, supporting its role as a tumor suppressor.
- Mechanistic studies suggest Resf1 is involved in transcriptional control, particularly in ribosomal biogenesis pathways, through association with G4 quadruplexes.
Conclusions:
- Resf1 is identified as a novel metastasis susceptibility gene in ER- breast cancer.
- Loss of Resf1 function promotes tumor progression and metastasis in ER- breast cancer.
- Resf1 may function as a tumor suppressor by regulating transcriptional and translational control, particularly ribosomal biogenesis.
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