Institute of Biomedical Sciences

Title

Rnaseh2c is a candidate metastasis susceptibility gene in breast cancer

Poster Number

15

Document Type

Poster

Keywords

Rnaseh2c, breast cancer, metastasis, immune response, mouse models

Publication Date

4-2017

Abstract

Metastatic breast cancer is a devastating disease with a 5-year survival rate of only 26%. This is due to a lack of effective therapies against established metastases and an inability to identify high risk patients who would benefit from specific adjuvant therapies to prevent metastatic progression. We have shown in mouse models that spontaneously arising tumors metastasize with different severity based on the mouse genetic background. Using systems genetics approaches we have identified genes correlated with metastasis and survival in both mice and humans. Rnaseh2c was identified as a novel candidate metastasis susceptibility gene. This gene encodes a scaffolding subunit of the Ribonuclease H2 enzyme which cleaves DNA at sites of misincorporated ribonucleotides to facilitate their removal. Experimentally modulating Rnaseh2c expression in a murine mammary cancer cell line resulted in significant changes in pulmonary metastasis, confirming this gene as a metastasis modifier. Mutations in Rnaseh2c are known to cause Aicardi-Goutieres Syndrome, a neurological autoinflammatory disorder that overlaps clinically with congenital viral infections and the autoimmune disease Systemic Lupus Erythematosus. Given this, we hypothesized that altered expression of Rnaseh2c in breast cancer cells affects metastasis by engaging the immune system. To investigate immune system involvement, we analyzed metastasis in immunocompromised mice. T cell deficiency ablated the effect of reduced Rnaseh2c expression on metastasis, revealing for the first time an Rnaseh2c-immune response axis in metastasis. Gene ontology pathway analysis following mRNA-sequencing of Rnaseh2c knockdown tumors revealed that 20% of the genes with altered expression are involved in immune system-related pathways, including T cell signaling and antigen presentation. Furthermore, genes with significant changes included Type I interferons, T cell markers, and immune regulators. These results confirm that Rnaseh2c is a novel metastasis modifier gene and validate our hypothesis that the immune system is mediating the effect of Rnaseh2c on metastasis. This mechanism highlights a potential new target for combination with immune modulatory therapies to combat this devastating disease and adds to a panel of genes we identified that together could determine patients with high risk for metastasis.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Open Access

1

Comments

To be presented at GW Annual Research Days 2017.

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Rnaseh2c is a candidate metastasis susceptibility gene in breast cancer

Metastatic breast cancer is a devastating disease with a 5-year survival rate of only 26%. This is due to a lack of effective therapies against established metastases and an inability to identify high risk patients who would benefit from specific adjuvant therapies to prevent metastatic progression. We have shown in mouse models that spontaneously arising tumors metastasize with different severity based on the mouse genetic background. Using systems genetics approaches we have identified genes correlated with metastasis and survival in both mice and humans. Rnaseh2c was identified as a novel candidate metastasis susceptibility gene. This gene encodes a scaffolding subunit of the Ribonuclease H2 enzyme which cleaves DNA at sites of misincorporated ribonucleotides to facilitate their removal. Experimentally modulating Rnaseh2c expression in a murine mammary cancer cell line resulted in significant changes in pulmonary metastasis, confirming this gene as a metastasis modifier. Mutations in Rnaseh2c are known to cause Aicardi-Goutieres Syndrome, a neurological autoinflammatory disorder that overlaps clinically with congenital viral infections and the autoimmune disease Systemic Lupus Erythematosus. Given this, we hypothesized that altered expression of Rnaseh2c in breast cancer cells affects metastasis by engaging the immune system. To investigate immune system involvement, we analyzed metastasis in immunocompromised mice. T cell deficiency ablated the effect of reduced Rnaseh2c expression on metastasis, revealing for the first time an Rnaseh2c-immune response axis in metastasis. Gene ontology pathway analysis following mRNA-sequencing of Rnaseh2c knockdown tumors revealed that 20% of the genes with altered expression are involved in immune system-related pathways, including T cell signaling and antigen presentation. Furthermore, genes with significant changes included Type I interferons, T cell markers, and immune regulators. These results confirm that Rnaseh2c is a novel metastasis modifier gene and validate our hypothesis that the immune system is mediating the effect of Rnaseh2c on metastasis. This mechanism highlights a potential new target for combination with immune modulatory therapies to combat this devastating disease and adds to a panel of genes we identified that together could determine patients with high risk for metastasis.