Abstract
Metastasis is a multi-step process that leads to the dissemination of tumor cells to new sites and, consequently, to multi-organ neoplasia. Although most lethal breast cancer cases are related to metastasis occurrence, little is known about the dysregulation of each step, and clinicians still lack reliable therapeutic targets for metastasis impairment. To fill these gaps, we constructed and analyzed gene regulatory networks for each metastasis step (cell adhesion loss, epithelial-to-mesenchymal transition, and angiogenesis). Through topological analysis, we identified E2F1, EGR1, EZH2, JUN, TP63, and miR-200c-3p as general hub-regulators, FLI1 for cell-adhesion loss specifically, and TRIM28, TCF3, and miR-429 for angiogenesis. Applying the FANMOD algorithm, we identified 60 coherent feed-forward loops regulating metastasis-related genes associated with distant metastasis-free survival prediction. miR-139-5p, miR-200c-3p, miR-454-3p, and miR-1301-3p, among others, were the FFL’s mediators. The expression of the regulators and mediators was observed to impact overall survival and to go along with metastasis occurrence. Lastly, we selected 12 key regulators and observed that they are potential therapeutic targets for canonical and candidate antineoplastics and immunomodulatory drugs, like trastuzumab, goserelin, and calcitriol. Our results highlight the relevance of miRNAs in mediating feed-forward loops and regulating the expression of metastasis-related genes. Altogether, our results contribute to understanding the multi-step metastasis complexity and identifying novel therapeutic targets and drugs for breast cancer management.
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All data utilized in this research are freely available in the referenced databases.
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Funding
This research was funded by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Process: 408730/2018-8.
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All authors contributed to the study conception and design. Alexandre Luiz Korte de Azevedo: conceptualization, formal analysis, investigation, writing—original draft, and visualization. Tamyres Mingorance Carvalho: formal analysis, investigation, and writing—original draft. Cristiane Sato Mara and Igor Samesima Giner: formal analysis and investigation. Daniela Fiore Gradia, Jaqueline Carvalho de Oliveira, Enilze Maria de Souza Fonseca Ribeiro, and Iglenir João Cavalli: conceptualization, writing—review and editing, and supervision.
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de Azevedo, A.L.K., Carvalho, T.M., Mara, C.S. et al. Major regulators of the multi-step metastatic process are potential therapeutic targets for breast cancer management. Funct Integr Genomics 23, 171 (2023). https://doi.org/10.1007/s10142-023-01097-x
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DOI: https://doi.org/10.1007/s10142-023-01097-x