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Breast cancer treatment can be improved with biomarkers for early detection and individualized therapy. A set of 86 microRNAs (miRNAs) were identified to separate breast cancer tumors from normal breast tissues (n = 52) with an overall accuracy of 90.4%. Six miRNAs had concordant expression in both tumors and breast cancer patient blood samples compared with the normal control samples. Twelve miRNAs showed concordant expression in tumors vs. normal breast tissues and patient survival (n = 1093), with seven as potential tumor suppressors and five as potential oncomiRs. From experimentally validated target genes of these 86 miRNAs, pan-sensitive and pan-resistant genes with concordant mRNA and protein expression associated with in-vitro drug response to 19 NCCN-recommended breast cancer drugs were selected. Combined with in-vitro proliferation assays using CRISPR-Cas9/RNAi and patient survival analysis, MEK inhibitors PD19830 and BRD-K12244279, pilocarpine, and tremorine were discovered as potential new drug options for treating breast cancer. Multi-omics biomarkers of response to the discovered drugs were identified using human breast cancer cell lines. This study presented an artificial intelligence pipeline of miRNA-based discovery of biomarkers, therapeutic targets, and repositioning drugs that can be applied to many cancer types.
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Targeting the Interplay between Epithelial-to-Mesenchymal-Transition and the Immune System for Effective Immunotherapy
Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) do not respond to immunotherapy, and many of them develop resistance to chemotherapy. Molecular characterization of non-responsive cancers suggest that an embryonic program known as epithelial-mesenchymal transition (EMT), which is mostly latent in adults, can be activated under selective pressures, rendering these cancers resistant to chemo- and immunotherapies. EMT can also drive tumor metastases, which in turn also suppress the cancer-fighting activity of cytotoxic T cells that traffic into the tumor, causing immunotherapy to fail. In this review, we compare and contrast immunotherapy treatment options of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We discuss why, despite breakthrough progress in immunotherapy, attaining predictable outcomes in the clinic is mostly an unsolved problem for these tumors. Although these two cancer types appear different based upon their tissues of origin and molecular classification, gene expression indicate that they possess many similarities. Patient tumors exhibit activation of EMT, and resulting stem cell properties in both these cancer types associate with metastasis and resistance to existing cancer therapies. In addition, the EMT transition in both these cancers plays a crucial role in immunosuppression, which exacerbates treatment resistance. To improve cancer-related survival we need to understand and circumvent, the mechanisms through which these tumors become therapy resistant. In this review, we discuss new information and complementary perspectives to inform combination treatment strategies to expand and improve the anti-tumor responses of currently available clinical immune checkpoint inhibitors.
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- Award ID(s):
- 1705464
- PAR ID:
- 10110680
- Author(s) / Creator(s):
- ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; more »
- Date Published:
- Journal Name:
- Cancers
- Volume:
- 11
- Issue:
- 5
- ISSN:
- 2072-6694
- Page Range / eLocation ID:
- 714
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript
- Journal Article:
- https://doi.org/10.3390/cancers11050714
