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SNRPD1 conveys prognostic value on breast cancer survival and is required for anthracycline sensitivity
Xiaofeng Dai1,2, Linhan Cai3, Zhifa Zhang3
1The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. xiaofengteam@163.com.
Background:
Cancers harboring spliceosome mutations are highly sensitive to additional perturbations on the spliceosome that leads to the development of onco-therapeutics targeting the spliceosome and opens novel opportunities for managing aggressive tumors lacking effective treatment options such as triple negative breast cancers. Being the core spliceosome associated proteins, SNRPD1 and SNRPE have been both proposed as therapeutic targets for breast cancer management. Yet, their differences regarding their prognostic and therapeutic use as well as roles during carcinogenesis are largely unreported.
Methods:
We conducted in silico analysis at gene expression and genetic levels to differentiate the clinical relevance of SNRPD1 and SNRPE, and explored their differential functionalities and molecular mechanistic associations with cancer in vitro.
Results:
We showed that high SNRPD1 gene expression was prognostic of poor breast cancer survival whereas SNRPE was not. The SNRPD1 expression quantitative trait loci, rs6733100, was found independently prognostic of breast cancer survival using TCGA data. Silencing either SNRPD1 or SNRPE independently suppressed the growth of breast cancer cells, but decreased migration was only observed in SNRPD1-silenced cells. Knocking down SNRPD1 but not SNRPE triggers doxorubicin resistance in triple negative breast cancer cells. Gene enrichment and network analyses revealed the dynamic regulatory role of SNRPD1 on cell cycle and genome stability, and the preventive role of SNRPE against cancer stemness that may neutralize its promotive role on cancer cell proliferation.
Conclusion:
Our results differentiated the functionalities of SNRPD1 and SNRPE at both prognostic and therapeutic levels, and preliminarily explained the driving mechanism that requires additional explorations and validations.
Insights
Spliceosome proteins SNRPD1 and SNRPE show distinct roles in breast cancer. High SNRPD1 expression predicts poor survival, while SNRPE does not, offering different therapeutic avenues for aggressive cancers.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Spliceosome mutations in cancer create therapeutic vulnerabilities, particularly in triple-negative breast cancer.
- SNRPD1 and SNRPE are core spliceosome proteins proposed as breast cancer therapeutic targets.
- Limited data exists on the differential prognostic and therapeutic roles of SNRPD1 and SNRPE in breast cancer.
Purpose of the Study:
- To differentiate the clinical relevance of SNRPD1 and SNRPE in breast cancer.
- To explore their distinct functionalities and molecular associations with cancer.
- To investigate their roles in breast cancer progression and treatment resistance.
Main Methods:
- In silico analysis of gene expression and genetic data.
- In vitro studies involving gene silencing (SNRPD1 and SNRPE).
- TCGA data analysis for prognostic significance of SNRPD1 expression quantitative trait loci.
- Gene enrichment and network analyses.
Main Results:
- High SNRPD1 expression is a poor prognostic marker for breast cancer survival; SNRPE is not.
- SNRPD1 expression quantitative trait loci (rs6733100) independently predicts survival.
- Silencing SNRPD1 or SNRPE suppressed cell growth; only SNRPD1 silencing reduced migration.
- SNRPD1 knockdown, not SNRPE, induced doxorubicin resistance in triple-negative breast cancer cells.
- SNRPD1 dynamically regulates cell cycle and genome stability; SNRPE may prevent cancer stemness.
Conclusions:
- SNRPD1 and SNRPE exhibit distinct prognostic and therapeutic implications in breast cancer.
- SNRPD1's role in cell cycle and genome stability contrasts with SNRPE's potential role in preventing cancer stemness.
- These findings provide a mechanistic basis for differential targeting strategies, requiring further validation.
