Analysis of miRNAs: Biomarkers for HER2-Targeted Breast Cancer Therapy

Thanh Hoa Vo; Orla O’Donovan; Edel McNeela; Jai Prakash Mehta; Sweta Rani

doi:10.21467/ias.13.1.29-41

Authors

Thanh Hoa Vo Department of Science, School of Science and Computing, South East Technological University, Ireland
Orla O’Donovan Department of Science, School of Science and Computing, South East Technological University, Ireland
Edel McNeela Department of Science, School of Science and Computing, South East Technological University, Ireland
Jai Prakash Mehta Pharmaceutical and Molecular Biotechnology Research Center, South East Technological University, Waterford, Ireland
Sweta Rani Department of Science, School of Science and Computing, South East Technological University, Ireland

DOI:

https://doi.org/10.21467/ias.13.1.29-41

Abstract

Breast cancer remains a leading lethal cancer in women globally, with the HER2+ positive subtype associated with a higher chance of therapeutic resistance. Treatments tailored specifically to this subtype, such as targeted therapies, have significantly developed over the past decade. However, the issue of drug resistance to targeted drugs underlines the necessity of better treatment approaches. Recent studies have focused on microRNAs (miRNAs), single-stranded non-coding RNAs, as critical regulators in drug resistance mechanisms. These miRNAs, capable of influencing various cellular processes, have emerged as critical modulators in numerous diseases, including different cancer types, particularly breast cancer. This article reviews current methodologies in the study of miRNAs within the context of HER2-positive breast cancer, from the selection of study models and sample extraction to comprehensive analysis methods. Our objective is to highlight the potential that miRNAs hold as biomarkers capable of regulating drug resistance in this specific cancer subtype. Moreover, we also discuss the importance of integrating advanced study models alongside the latest bioinformatics tools to enrich this research domain. Furthermore, this article evaluates the use of clinical samples and cell line models for studying miRNAs in this field, outlining the advantages and limitations of each method and proposing a refined approach to research design. The main contribution of this work is the establishment of a detailed taxonomy of research strategies that address current challenges while also outlining promising future directions, particularly focused on elucidating the regulatory mechanisms of miRNAs in therapeutic resistance in breast cancer. In addition, by underscoring the necessity of employing a diverse array of study models and capitalizing on bioinformatics advancements, this article seeks to uncover the complex interactions between miRNAs and drug resistance mechanisms in breast cancer. Ultimately, our goal is to pave the way toward overcoming therapeutic resistance, thereby improving the prognosis for patients afflicted with HER2-positive breast cancer.

Keywords:

HER2-positive breast cancer, miRNAs, Treatment response, Targeted-drugs

Downloads

Download data is not yet available.

References

C. J. Witton, J. R. Reeves, J. J. Going, T. Cooke, and J. M. S. Bartlett, "Expression of the HER1–4 family of receptor tyrosine kinases in breast cancer," The Journal of Pathology, vol. 200, 2003.

D. J. Slamon et al., "Adjuvant trastuzumab in HER2-positive breast cancer," The New England journal of medicine, vol. 365 14, pp. 1273-83, 2011.

X. Dai, L. Xiang, T. Li, and Z. Bai, "Cancer Hallmarks, Biomarkers and Breast Cancer Molecular Subtypes," J Cancer, vol. 7, no. 10, pp. 1281-94, 2016.

K. Greenblatt and K. Khaddour, "Trastuzumab," in StatPearls. Treasure Island (FL): StatPearls Publishing, 2023.

S. J. Malenfant, K. R. Eckmann, and C. M. Barnett, "Pertuzumab: a new targeted therapy for HER2-positive metastatic breast cancer," Pharmacotherapy, vol. 34, no. 1, pp. 60-71, 2014.

S. Verma et al., "Trastuzumab emtansine for HER2-positive advanced breast cancer," N Engl J Med, vol. 367, no. 19, pp. 1783-91, 2012.

J. Jones, A. Takeda, J. Picot, C. von Keyserlingk, and A. Clegg, "Lapatinib for the treatment of HER2-overexpressing breast cancer," Health Technol Assess, vol. 13 Suppl 3, pp. 1-6, 2009.

R. Paranjpe et al., "Neratinib in HER2-Positive Breast Cancer Patients," Annals of Pharmacotherapy, vol. 53, pp. 612 - 620, 2019.

R. C. Lee, R. L. Feinbaum, and V. Ambros, "The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14," Cell, vol. 75, no. 5, pp. 843-54, 1993.

B. J. Reinhart et al., "The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans," Nature, vol. 403, no. 6772, pp. 901-6, 2000.

K. U. Tüfekci, R. L. Meuwissen, and S. Genç, "The role of microRNAs in biological processes," Methods Mol Biol, vol. 1107, pp. 15-31, 2014.

S. Mishra, T. Yadav, and V. Rani, "Exploring miRNA based approaches in cancer diagnostics and therapeutics," Crit Rev Oncol Hematol, vol. 98, pp. 12-23, 2016.

M. Hill and N. Tran, "miRNA interplay: mechanisms and consequences in cancer," Dis Model Mech, vol. 14, no. 4, 2021.

A. McGuire, J. A. Brown, and M. J. Kerin, "Metastatic breast cancer: the potential of miRNA for diagnosis and treatment monitoring," Cancer Metastasis Rev, vol. 34, no. 1, pp. 145-55, 2015.

B. J. Petri and C. M. Klinge, "Regulation of breast cancer metastasis signaling by miRNAs," Cancer Metastasis Rev, vol. 39, no. 3, pp. 837-886, 2020.

H. Sabit, E. Cevik, H. Tombuloglu, S. Abdel-Ghany, G. Tombuloglu, and M. Esteller, "Triple negative breast cancer in the era of miRNA," Crit Rev Oncol Hematol, vol. 157, p. 103196, 2021.

I. Fridrichova and I. Zmetakova, "MicroRNAs Contribute to Breast Cancer Invasiveness," Cells, vol. 8, no. 11, 2019.

V. Fogazzi et al., "The Role of MicroRNAs in HER2-Positive Breast Cancer: Where We Are and Future Prospective," Cancers (Basel), vol. 14, no. 21, 2022.

S. E. Wang and R. J. Lin, "MicroRNA and HER2-overexpressing cancer," Microrna, vol. 2, no. 2, pp. 137-47, 2013.

L. Luo et al., "Disruption of FOXO3a-miRNA feedback inhibition of IGF2/IGF-1R/IRS1 signaling confers Herceptin resistance in HER2-positive breast cancer," Nat Commun, vol. 12, no. 1, p. 2699, 2021.

M. Han et al., "Exosome-transmitted miR-567 reverses trastuzumab resistance by inhibiting ATG5 in breast cancer," Cell Death Dis, vol. 11, no. 1, p. 43, 2020.

T. Ma, L. Yang, and J. Zhang, "MiRNA‑542‑3p downregulation promotes trastuzumab resistance in breast cancer cells via AKT activation," Oncol Rep, vol. 33, no. 3, pp. 1215-20, 2015.

A. Allegra et al., "Circulating microRNAs: new biomarkers in diagnosis, prognosis and treatment of cancer (review)," Int J Oncol, vol. 41, no. 6, pp. 1897-912, 2012.

E. J. Jung et al., "Plasma microRNA 210 levels correlate with sensitivity to trastuzumab and tumor presence in breast cancer patients," Cancer, vol. 118, no. 10, pp. 2603-14, 2012.

X. Lu et al., "MiR-129-5p Sensitizes the Response of Her-2 Positive Breast Cancer to Trastuzumab by Reducing Rps6," Cellular Physiology and Biochemistry, vol. 44, no. 6, pp. 2346-2356, 2017.

M. Zhang, Z. Li, and X. Liu, "MiR-98-5p/IGF2 Axis Influence Herceptin Sensitivity through IGF1R/HER2 Heterodimer Formation and AKT/mTOR Signal Pathway in HER2 Positive Breast Cancer," Asian Pac J Cancer Prev, vol. 22, no. 11, pp. 3693-3703, 2021.

J. Hayes, P. P. Peruzzi, and S. Lawler, "MicroRNAs in cancer: biomarkers, functions and therapy," Trends in Molecular Medicine, vol. 20, no. 8, pp. 460-469, 2014.

S. Ameling et al., "Associations of circulating plasma microRNAs with age, body mass index and sex in a population-based study," BMC Med Genomics, vol. 8, p. 61, 2015.

H. C. de Boer et al., "Aspirin treatment hampers the use of plasma microRNA-126 as a biomarker for the progression of vascular disease," European Heart Journal, vol. 34, no. 44, pp. 3451-3457, 2013.

E. Flowers, G. Y. Won, and Y. Fukuoka, "MicroRNAs associated with exercise and diet: a systematic review," Physiological Genomics, vol. 47, no. 1, pp. 1-11, 2015.

X. Ye et al., "MiR-221 promotes trastuzumab-resistance and metastasis in HER2-positive breast cancers by targeting PTEN," BMB Rep, vol. 47, no. 5, pp. 268-73, 2014.

L. De Mattos-Arruda et al., "MicroRNA-21 links epithelial-to-mesenchymal transition and inflammatory signals to confer resistance to neoadjuvant trastuzumab and chemotherapy in HER2-positive breast cancer patients," Oncotarget, vol. 6, no. 35, pp. 37269-80, 2015.

C. C. Pritchard, H. H. Cheng, and M. Tewari, "MicroRNA profiling: approaches and considerations," Nature Reviews Genetics, vol. 13, no. 5, pp. 358-369, 2012.

H.-J. Wu and P.-Y. Chu, "Current and Developing Liquid Biopsy Techniques for Breast Cancer," Cancers, vol. 14, no. 9, p. 2052, 2022.

C. Cui and Q. Cui, "The relationship of human tissue microRNAs with those from body fluids," Scientific Reports, vol. 10, no. 1, p. 5644, 2020.

L. H. Chi et al., "MicroRNA-21 is immunosuppressive and pro-metastatic via separate mechanisms," Oncogenesis, vol. 11, no. 1, p. 38, 2022.

C. Corcoran et al., "miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer," Molecular Cancer, vol. 13, no. 1, p. 71, 2014.

F. C. Huynh and F. E. Jones, "MicroRNA-7 Inhibits Multiple Oncogenic Pathways to Suppress HER2Δ16 Mediated Breast Tumorigenesis and Reverse Trastuzumab Resistance," PLOS ONE, vol. 9, no. 12, p. e114419, 2014.

C. Ríos-Luci, E. Díaz-Rodríguez, L. Gandullo-Sánchez, L. Díaz-Gil, A. Ocaña, and A. Pandiella, "Adaptive resistance to trastuzumab impairs response to neratinib and lapatinib through deregulation of cell death mechanisms," Cancer Letters, vol. 470, pp. 161-169, 2020.

D. Yue and X. Qin, "miR-182 regulates trastuzumab resistance by targeting MET in breast cancer cells," Cancer Gene Therapy, vol. 26, no. 1, pp. 1-10, 2019.

F. W. Hunter et al., "Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer," British Journal of Cancer, vol. 122, no. 5, pp. 603-612, 2020.

T. K. Huynh et al., "miR-221 confers lapatinib resistance by negatively regulating p27(kip1) in HER2-positive breast cancer," Cancer Sci, vol. 112, no. 10, pp. 4234-4245, 2021.

P. Mirabelli, L. Coppola, and M. Salvatore, "Cancer Cell Lines Are Useful Model Systems for Medical Research," Cancers (Basel), vol. 11, no. 8, 2019.

M. Lacroix and G. Leclercq, "Relevance of breast cancer cell lines as models for breast tumours: an update," Breast Cancer Res Treat, vol. 83, no. 3, pp. 249-89, 2004.

D. L. Holliday and V. Speirs, "Choosing the right cell line for breast cancer research," Breast Cancer Research, vol. 13, no. 4, p. 215, 2011.

F. Balzano et al., "miRNA Stability in Frozen Plasma Samples," Molecules, vol. 20, no. 10, pp. 19030-19040, 2015.

X. Chen et al., "Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases," Cell Research, vol. 18, no. 10, pp. 997-1006, 2008.

M. B. Kirschner, N. van Zandwijk, and G. Reid, "Cell-free microRNAs: potential biomarkers in need of standardized reporting," Front Genet, vol. 4, p. 56, 2013.

R. A. M. Brown, M. R. Epis, J. L. Horsham, T. D. Kabir, K. L. Richardson, and P. J. Leedman, "Total RNA extraction from tissues for microRNA and target gene expression analysis: not all kits are created equal," BMC Biotechnology, vol. 18, no. 1, p. 16, 2018.

L. Valihrach, P. Androvic, and M. Kubista, "Circulating miRNA analysis for cancer diagnostics and therapy," Mol Aspects Med, vol. 72, p. 100825, 2020.

Y. Li and K. V. Kowdley, "Method for microRNA isolation from clinical serum samples," Analytical Biochemistry, vol. 431, no. 1, pp. 69-75, 2012.

V. Zelli et al., "Emerging Role of isomiRs in Cancer: State of the Art and Recent Advances," Genes (Basel), vol. 12, no. 9, 2021.

G. Han, N. Qiu, K. Luo, H. Liang, and H. Li, "Downregulation of miroRNA-141 mediates acquired resistance to trastuzumab and is associated with poor outcome in breast cancer by upregulating the expression of ERBB4," J Cell Biochem, 2019.

A. De Cola et al., "miR-205-5p-mediated downregulation of ErbB/HER receptors in breast cancer stem cells results in targeted therapy resistance," Cell Death Dis, vol. 6, no. 7, p. e1823, 2015.

W.-D. Bai et al., "MiR-200c suppresses TGF-β signaling and counteracts trastuzumab resistance and metastasis by targeting ZNF217 and ZEB1 in breast cancer," International Journal of Cancer, vol. 135, no. 6, pp. 1356-1368, 2014.

C. A. Ball et al., "Standards for Microarray Data," Science, vol. 298, no. 5593, pp. 539-539, 2002.

C. G. Liu, G. A. Calin, S. Volinia, and C. M. Croce, "MicroRNA expression profiling using microarrays," Nat Protoc, vol. 3, no. 4, pp. 563-78, 2008.

J. Q. Yin, R. C. Zhao, and K. V. Morris, "Profiling microRNA expression with microarrays," Trends in Biotechnology, vol. 26, no. 2, pp. 70-76, 2008.

V. Bolón-Canedo, A. Alonso-Betanzos, I. López-de-Ullibarri, and R. Cao, "Challenges and Future Trends for Microarray Analysis," Methods Mol Biol, vol. 1986, pp. 283-293, 2019.

T. Siddika and I. U. Heinemann, "Bringing MicroRNAs to Light: Methods for MicroRNA Quantification and Visualization in Live Cells," Frontiers in Bioengineering and Biotechnology, Review vol. 8, 2021.

P. Chugh and D. P. Dittmer, "Potential pitfalls in microRNA profiling," WIREs RNA, vol. 3, no. 5, pp. 601-616, 2012.

E. M. Kroh, R. K. Parkin, P. S. Mitchell, and M. Tewari, "Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR)," Methods, vol. 50, no. 4, pp. 298-301, 2010.

M. Kubista et al., "The real-time polymerase chain reaction," Mol Aspects Med, vol. 27, no. 2-3, pp. 95-125, 2006.

P. S. Bernard and C. T. Wittwer, "Real-Time PCR Technology for Cancer Diagnostics," Clinical Chemistry, vol. 48, no. 8, pp. 1178-1185, 2002.

S. Mocellin, C. R. Rossi, P. Pilati, D. Nitti, and F. M. Marincola, "Quantitative real-time PCR: a powerful ally in cancer research," Trends Mol Med, vol. 9, no. 5, pp. 189-95, 2003.

K. G. Renz, A. Islam, B. F. Cheetham, and S. W. Walkden-Brown, "Absolute quantification using real-time polymerase chain reaction of Marek's disease virus serotype 2 in field dust samples, feather tips and spleens," Journal of Virological Methods, vol. 135, no. 2, pp. 186-191, 2006.

D. A. Forero, Y. González-Giraldo, L. J. Castro-Vega, and G. E. Barreto, "qPCR-based methods for expression analysis of miRNAs," Biotechniques, vol. 67, no. 4, pp. 192-199, 2019.

C. Chen et al., "Real-time quantification of microRNAs by stem-loop RT-PCR," Nucleic Acids Res, vol. 33, no. 20, p. e179, 2005.

R. Shi and V. L. Chiang, "Facile means for quantifying microRNA expression by real-time PCR," Biotechniques, vol. 39, no. 4, pp. 519-25, 2005.

P. Kumar, B. H. Johnston, and S. A. Kazakov, "miR-ID: a novel, circularization-based platform for detection of microRNAs," Rna, vol. 17, no. 2, pp. 365-80, 2011.

S. A. Bustin and T. Nolan, "Pitfalls of quantitative real-time reverse-transcription polymerase chain reaction," J Biomol Tech, vol. 15, no. 3, pp. 155-66, 2004.

M. Chen, G. A. Calin, and Q. H. Meng, "Chapter Five - Circulating microRNAs as Promising Tumor Biomarkers," in Advances in Clinical Chemistry, vol. 67, G. S. Makowski Ed.: Elsevier, 2014, pp. 189-214.

E. A. Hunt, D. Broyles, T. Head, and S. K. Deo, "MicroRNA Detection: Current Technology and Research Strategies," Annual Review of Analytical Chemistry, vol. 8, no. 1, pp. 217-237, 2015.

F. Vigneault et al., "High-throughput multiplex sequencing of miRNA," Curr Protoc Hum Genet, vol. Chapter 11, pp. 11.12.1-11.12.10, 2012.

T. A. Karlsen, T. F. Aae, and J. E. Brinchmann, "Robust profiling of microRNAs and isomiRs in human plasma exosomes across 46 individuals," Scientific Reports, vol. 9, no. 1, p. 19999, 2019.

N. Ludwig et al., "Bias in recent miRBase annotations potentially associated with RNA quality issues," Sci Rep, vol. 7, no. 1, p. 5162, 2017.

L. Venturutti et al., "MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1," Oncogene, vol. 35, no. 48, pp. 6189-6202, 2016.

Z. Zhang et al., "Exosomal miR-1246 and miR-155 as predictive and prognostic biomarkers for trastuzumab-based therapy resistance in HER2-positive breast cancer," Cancer Chemother Pharmacol, vol. 86, no. 6, pp. 761-772, 2020.

H. Li et al., "A serum microRNA signature predicts trastuzumab benefit in HER2-positive metastatic breast cancer patients," Nat Commun, vol. 9, no. 1, p. 1614, 2018.

L. Luo et al., "Disruption of FOXO3a-miRNA feedback inhibition of IGF2/IGF-1R/IRS1 signaling confers Herceptin resistance in HER2-positive breast cancer," Nature Communications, vol. 12, no. 1, p. 2699, 2021.

G. Han, N. Qiu, K. Luo, H. Liang, and H. Li, "Downregulation of miroRNA-141 mediates acquired resistance to trastuzumab and is associated with poor outcome in breast cancer by upregulating the expression of ERBB4," J Cell Biochem, vol. 120, no. 7, pp. 11390-11400, 2019.

X. M. Ye et al., "Epigenetic silencing of miR-375 induces trastuzumab resistance in HER2-positive breast cancer by targeting IGF1R," BMC Cancer, vol. 14, p. 134, 2014.

C. Corcoran et al., "miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer," Mol Cancer, vol. 13, p. 71, 2014.

A. De Cola et al., "miR-205-5p-mediated downregulation of ErbB/HER receptors in breast cancer stem cells results in targeted therapy resistance," Cell Death & Disease, vol. 6, no. 7, pp. e1823-e1823, 2015.

D. R. Boulbès, G. B. Chauhan, Q. Jin, C. Bartholomeusz, and F. J. Esteva, "CD44 expression contributes to trastuzumab resistance in HER2-positive breast cancer cells," Breast Cancer Research and Treatment, vol. 151, pp. 501-513, 2015.

W. D. Bai et al., "MiR-200c suppresses TGF-β signaling and counteracts trastuzumab resistance and metastasis by targeting ZNF217 and ZEB1 in breast cancer," Int J Cancer, vol. 135, no. 6, pp. 1356-68, 2014.

M. Han et al., "Exosome-transmitted miR-567 reverses trastuzumab resistance by inhibiting ATG5 in breast cancer," Cell Death & Disease, vol. 11, no. 1, p. 43, 2020.

Z. Li, Y. Qin, P. Chen, Q. Luo, H. Shi, and X. Jiang, "miR‑135b‑5p enhances the sensitivity of HER‑2 positive breast cancer to trastuzumab via binding to cyclin D2," Int J Mol Med, vol. 46, no. 4, pp. 1514-1524, 2020.

X. Lu et al., "MiR-129-5p Sensitizes the Response of Her-2 Positive Breast Cancer to Trastuzumab by Reducing Rps6," Cell Physiol Biochem, vol. 44, no. 6, pp. 2346-2356, 2017.

S. Noyan, H. Gurdal, and B. Gur Dedeoglu, "Involvement of miR-770-5p in trastuzumab response in HER2 positive breast cancer cells," PLoS One, vol. 14, no. 4, p. e0215894, 2019.

S. Sajadimajd, R. Yazdanparast, and S. Akram, "Involvement of Numb-mediated HIF-1α inhibition in anti-proliferative effect of PNA-antimiR-182 in trastuzumab-sensitive and -resistant SKBR3 cells," Tumour Biol, vol. 37, no. 4, pp. 5413-26, 2016.

E. Tormo et al., "The role of miR-26a and miR-30b in HER2+ breast cancer trastuzumab resistance and regulation of the CCNE2 gene," Scientific Reports, vol. 7, no. 1, p. 41309, 2017.

S. Ergün et al., "The association of the expression of miR-122-5p and its target ADAM10 with human breast cancer," Molecular Biology Reports, vol. 42, no. 2, pp. 497-505, 2015.

A. Garcia-Moreno and P. Carmona-Saez, "Computational Methods and Software Tools for Functional Analysis of miRNA Data," Biomolecules, vol. 10, no. 9, 2020.

K. Wang, Y. Yuan, J. H. Cho, S. McClarty, D. Baxter, and D. J. Galas, "Comparing the MicroRNA spectrum between serum and plasma," PLoS One, vol. 7, no. 7, p. e41561, 2012.

M. Ravi, V. Paramesh, S. R. Kaviya, E. Anuradha, and F. D. Solomon, "3D cell culture systems: advantages and applications," J Cell Physiol, vol. 230, no. 1, pp. 16-26, 2015.

Y. Liu, W. Wu, C. Cai, H. Zhang, H. Shen, and Y. Han, "Patient-derived xenograft models in cancer therapy: technologies and applications," Signal Transduction and Targeted Therapy, vol. 8, no. 1, p. 160, 2023.

R. J. Porter, G. I. Murray, and M. H. McLean, "Current concepts in tumour-derived organoids," British Journal of Cancer, vol. 123, no. 8, pp. 1209-1218, 2020.

G. Trujillo-de Santiago et al., "The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors," Materials (Basel), vol. 12, no. 18, 2019.

D. P. Saraiva, A. T. Matias, S. Braga, A. Jacinto, and M. G. Cabral, "Establishment of a 3D Co-culture With MDA-MB-231 Breast Cancer Cell Line and Patient-Derived Immune Cells for Application in the Development of Immunotherapies," Front Oncol, vol. 10, p. 1543, 2020.