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Therapeutic Potential of Chemically Modified miR-489 in Triple-Negative Breast Cancers
Young Hwa Soung1, Heesung Chung1,2, Cecilia Yan1
1Department of Pathology, Stony Brook Medicine, Stony Brook, NY 11794, USA.
Abstract:
Triple-negative breast cancers (TNBCs) lack ER, PR and her2 receptors that are targets of common breast cancer therapies with poor prognosis due to their high rates of metastasis and chemoresistance. Based on our previous studies that epigenetic silencing of a potential metastasis suppressor, arrestin domain-containing 3 (ARRDC3), is linked to the aggressive nature of TNBCs, we identified a sub-group of tumor suppressing miRNAs whose expressions were significantly up-regulated by ARRDC3 over-expression in TNBC cells. Among these tumor suppressing miRs, we found that miR-489 is most anti-proliferative in TNBC cells. miR-489 also blocked DNA damaging responses (DDRs) in TNBC cells. To define the mechanism by which miR-489 inhibits TNBC cell functions, we screened the potential target genes of miR-489 and identified MDC-1 and SUZ-12 as novel target genes of miR-489 in TNBC cells. To further exploit the therapeutic potentials of miR-489 in TNBC models, we chemically modified the guide strand of miR-489 (CMM489) by replacing Uracil with 5-fluorouracil (5-FU) so that tumor suppressor (miR-489) and DNA damaging (5-FU) components are combined into a single agent as a novel drug candidate for TNBCs. Our studies demonstrated that CMM489 shows superior effects over miR-489 or 5-FU in inhibition of TNBC cell proliferation and tumor progression, suggesting its therapeutic efficacy in TNBC models.
Insights
Triple-negative breast cancer (TNBC) is aggressive. Researchers found miR-489 inhibits TNBC growth and developed a novel drug, CMM489, combining miR-489 with 5-FU for superior therapeutic effects.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapies and exhibits aggressive metastasis and chemoresistance.
- Epigenetic silencing of arrestin domain-containing 3 (ARRDC3) correlates with TNBC aggressiveness.
- ARRDC3 up-regulates tumor-suppressing microRNAs (miRNAs) in TNBC cells.
Purpose of the Study:
- To identify and characterize tumor-suppressing miRNAs in TNBC.
- To investigate the anti-proliferative and DNA damage response inhibitory mechanisms of miR-489 in TNBC.
- To develop a novel therapeutic agent for TNBC by combining miR-489 with a chemotherapeutic drug.
Main Methods:
- Over-expression of ARRDC3 in TNBC cells to identify upregulated miRNAs.
- Screening of miR-489 target genes, including MDC-1 and SUZ-12.
- Chemical modification of miR-489 (CMM489) by incorporating 5-fluorouracil (5-FU).
- Evaluation of CMM489 efficacy in TNBC cell proliferation and tumor progression models.
Main Results:
- miR-489 demonstrated significant anti-proliferative activity and blocked DNA damaging responses in TNBC cells.
- MDC-1 and SUZ-12 were identified as novel direct targets of miR-489 in TNBC.
- The novel drug candidate CMM489 exhibited superior efficacy compared to miR-489 or 5-FU alone in inhibiting TNBC proliferation and progression.
Conclusions:
- miR-489 acts as a potent tumor suppressor in TNBC by targeting MDC-1 and SUZ-12.
- CMM489 represents a promising single-agent therapeutic strategy for TNBC, combining tumor suppression and DNA damage.
- This study highlights the therapeutic potential of miR-489 and its derivatives for aggressive TNBC subtypes.
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