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Identification of tRNA-derived small RNA (tsRNA) responsive to the tumor suppressor, RUNX1, in breast cancer
Nicholas H Farina1,2,3, Stephanie Scalia3,4, Caroline E Adams3,4
1Department of Biochemistry, Larner College of Medicine, University of Vermont, Burlington, Vermont.
Abstract:
Despite recent advances in targeted therapies, the molecular mechanisms driving breast cancer initiation, progression, and metastasis are minimally understood. Growing evidence indicate that transfer RNA (tRNA)-derived small RNAs (tsRNA) contribute to biological control and aberrations associated with cancer development and progression. The runt-related transcription factor 1 (RUNX1) transcription factor is a tumor suppressor in the mammary epithelium whereas RUNX1 downregulation is functionally associated with breast cancer initiation and progression. We identified four tsRNA (ts-19, ts-29, ts-46, and ts-112) that are selectively responsive to expression of the RUNX1 tumor suppressor. Our finding that ts-112 and RUNX1 anticorrelate in normal-like mammary epithelial and breast cancer lines is consistent with tumor-related activity of ts-112 and tumor suppressor activity of RUNX1. Inhibition of ts-112 in MCF10CA1a aggressive breast cancer cells significantly reduced proliferation. Ectopic expression of a ts-112 mimic in normal-like mammary epithelial MCF10A cells significantly increased proliferation. These findings support an oncogenic potential for ts-112. Moreover, RUNX1 may repress ts-112 to prevent overactive proliferation in breast epithelial cells to augment its established roles in maintaining the mammary epithelium.
Insights
Transfer RNA-derived small RNAs (tsRNAs) influence breast cancer. Researchers found ts-112 promotes proliferation, suggesting it acts as an oncogene, while RUNX1 may suppress it.
Area of Science:
- Molecular biology
- Oncology
- Genetics
Background:
- Breast cancer progression mechanisms remain unclear.
- Transfer RNA-derived small RNAs (tsRNAs) are implicated in cancer.
- RUNX1 is a tumor suppressor in mammary epithelium, with its downregulation linked to breast cancer.
Purpose of the Study:
- To investigate the role of tsRNAs in breast cancer.
- To identify tsRNAs regulated by the RUNX1 tumor suppressor.
- To explore the functional significance of ts-112 in breast cancer.
Main Methods:
- Identification of tsRNAs responsive to RUNX1 expression.
- Analysis of ts-112 and RUNX1 correlation in mammary cell lines.
- Functional assays involving ts-112 inhibition and mimic expression.
Main Results:
- Four tsRNAs (ts-19, ts-29, ts-46, ts-112) were identified as responsive to RUNX1.
- ts-112 expression inversely correlated with RUNX1 in normal and cancerous mammary cells.
- ts-112 inhibition reduced proliferation in aggressive breast cancer cells.
- ts-112 mimic expression increased proliferation in normal mammary epithelial cells.
Conclusions:
- ts-112 exhibits oncogenic potential, promoting breast cancer cell proliferation.
- RUNX1 may exert tumor suppressive functions by repressing ts-112.
- These findings highlight a novel regulatory axis involving RUNX1 and ts-112 in breast cancer.
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