School of Medicine and Health Sciences Poster Presentations
Rnaseh2c is a Candidate Metastasis Susceptibility Gene in Breast Cancer
Poster Number
18
Document Type
Poster
Publication Date
3-2016
Abstract
While 5-year survival for localized breast cancer is around 98%, survival for patients with metastatic disease plummets to 26%. This statistic indicates that the majority of mortality associated with breast cancer is due to metastatic disease, for which no targeted treatments are available. One of factors that affects whether a patient will develop metastases is genetics. We have previously shown using mouse models that the genetic background on which a tumor arises significantly influences its metastatic capacity. Furthermore, we have used a haplotype mapping approach to identify candidate genes whose expression in tumors correlates with metastasis. One of these candidates, Rnaseh2c, had expression positively correlated with metastasis. Interestingly, Rnaseh2c has not been previously linked to cancer or metastasis prior to our analysis. This gene encodes a scaffolding subunit of the Ribonuclease H2 enzyme which removes ribonucleotides that have been misincorporated into the DNA. Mutations in this gene are known to cause the neurological autoinflammatory disorder Aicardi-Goutieres Syndrome (AGS). This disease overlaps clinically with congenital viral infections and the autoimmune disease System Lupus Erythematosus. Given this information, we hypothesized that altering the expression of Rnaseh2c in breast cancer cells affects metastasis by engaging the immune system. Modulating the expression of RNASEH2C using shRNAs and exogenous expression vectors in a murine mammary cancer cell line resulted in significant changes in pulmonary metastasis, confirming this gene as a metastasis modifier. In order to investigate immune system involvement, we analyzed metastasis in immunocompromised mice. T cell deficiency ablated the effect of reduced RNASEH2C expression on metastasis, supporting our hypothesis that the immune system is involved in mediating the metastatic effect. We also performed mRNA-sequencing to achieve an unbiased survey of gene expression changes in response to altering RNASEH2C expression. Gene ontology pathway analysis revealed that 20% of the genes exhibiting altered expression between tumors with RNASEH2C knockdown versus overexpression are involved in immune system-related pathways including T cell signaling and antigen presentation. In addition, some of the genes with significant changes were Type I interferons, T cell surface markers, and immune response regulators. Together these results confirm Rnaseh2c as a novel metastasis modifier gene and support our hypothesis that its effect on metastasis is mediated by the immune system. This mechanism may highlight a new target for immune modulatory therapies to combat the devastating outcome of metastatic breast cancer.
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Rnaseh2c is a Candidate Metastasis Susceptibility Gene in Breast Cancer
While 5-year survival for localized breast cancer is around 98%, survival for patients with metastatic disease plummets to 26%. This statistic indicates that the majority of mortality associated with breast cancer is due to metastatic disease, for which no targeted treatments are available. One of factors that affects whether a patient will develop metastases is genetics. We have previously shown using mouse models that the genetic background on which a tumor arises significantly influences its metastatic capacity. Furthermore, we have used a haplotype mapping approach to identify candidate genes whose expression in tumors correlates with metastasis. One of these candidates, Rnaseh2c, had expression positively correlated with metastasis. Interestingly, Rnaseh2c has not been previously linked to cancer or metastasis prior to our analysis. This gene encodes a scaffolding subunit of the Ribonuclease H2 enzyme which removes ribonucleotides that have been misincorporated into the DNA. Mutations in this gene are known to cause the neurological autoinflammatory disorder Aicardi-Goutieres Syndrome (AGS). This disease overlaps clinically with congenital viral infections and the autoimmune disease System Lupus Erythematosus. Given this information, we hypothesized that altering the expression of Rnaseh2c in breast cancer cells affects metastasis by engaging the immune system. Modulating the expression of RNASEH2C using shRNAs and exogenous expression vectors in a murine mammary cancer cell line resulted in significant changes in pulmonary metastasis, confirming this gene as a metastasis modifier. In order to investigate immune system involvement, we analyzed metastasis in immunocompromised mice. T cell deficiency ablated the effect of reduced RNASEH2C expression on metastasis, supporting our hypothesis that the immune system is involved in mediating the metastatic effect. We also performed mRNA-sequencing to achieve an unbiased survey of gene expression changes in response to altering RNASEH2C expression. Gene ontology pathway analysis revealed that 20% of the genes exhibiting altered expression between tumors with RNASEH2C knockdown versus overexpression are involved in immune system-related pathways including T cell signaling and antigen presentation. In addition, some of the genes with significant changes were Type I interferons, T cell surface markers, and immune response regulators. Together these results confirm Rnaseh2c as a novel metastasis modifier gene and support our hypothesis that its effect on metastasis is mediated by the immune system. This mechanism may highlight a new target for immune modulatory therapies to combat the devastating outcome of metastatic breast cancer.
Comments
Presented at: GW Research Days 2016