Abstract
Background: Metastasis is a leading cause of breast cancer mortality. The induction of epithelial-to-mesenchymal transition (EMT) and complex oncogenic signaling is a vital step in the evolution of highly metastatic and therapeutically-intractable breast cancer; necessitating novel target discovery or development of therapeutics that target metastatic breast cells (MBCs). Methods: To achieve this, this study employs a combination of in silico bioinformatics analyses, protein and transcript analyses, drug sensitivity assays, functional assays and animal studies. Results: The present study identified CDH11 as an inductor and/or facilitator of metastatic signaling, and biomarker of poor prognosis in MBCs. Furthermore, we showed that in the presence of CDH11-rich cancer-associated fibroblasts (CAFs), MCF7 and MDA-MB-231 MBC cell lines acquired enhanced metastatic phenotype with increased CDH11, β-catenin, vimentin, and fibronectin (FN) expression. We also demonstrated, for the first time to the best of our knowledge that exposure to anti-CDH11 antibody suppresses metastasis, reduces CDH11, FN and β-catenin expression, and abrogate the cancer stem cell (CSC)-like traits of MBC cells. Interestingly, ectopic expression of miR-335 suppressed CDH11, β-catenin and vimentin expression, in concert with attenuated metastatic and CSC potentials of the MBC cells; conversely, inhibition of miR-335 resulted in increased metastatic potential. Finally, corroborating the in silica and in vitro findings, in vivo assays showed that the administration of anti-CDH11 antibody or miR-335 mimic suppressed tumorigenesis and inhibited cancer metastasis. Conclusions: These findings validate our hypotheses that miR-335 mediates anti-CDH11 antibody therapy response and that an enhanced miR-335/CDH11 ratio elicits marked suppression of the MBC CSC-like and metastatic phenotypes, thus revealing a therapeutically-exploitable inverse correlation between CDH11-enhanced CSC-like and metastatic phenotype and miR-335 expression in MBCs. Thus, we highlight the therapeutic promise of humanized anti-CDH11 antibodies or miR-335-mimic, making a case for their clinical application as efficacious therapeutic option in patients with MBC.
Original language | English |
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Article number | 5811 |
Journal | BMC Cancer |
Volume | 19 |
Issue number | 1 |
DOIs | |
Publication status | Published - Jun 27 2019 |
Keywords
- Antibody therapeutics
- Cancer stem cell
- CDH11/β-catenin signaling
- Invasive breast cancer
- Metastasis
- miR-335
ASJC Scopus subject areas
- Genetics
- Oncology
- Cancer Research
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Additional file 2: of Monospecific antibody targeting of CDH11 inhibits epithelial-to-mesenchymal transition and represses cancer stem cell-like phenotype by up-regulating miR-335 in metastatic breast cancer, in vitro and in vivo
Chao, T. (Contributor), Chang, P. M. (Creator), Bamodu, O. A. (Contributor), Huang, W. (Contributor), Chen, J. (Creator) & Huang, T. (Contributor), Figshare, 2019
DOI: 10.6084/m9.figshare.8341991.v1, https://doi.org/10.6084%2Fm9.figshare.8341991.v1
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Additional file 1: of Monospecific antibody targeting of CDH11 inhibits epithelial-to-mesenchymal transition and represses cancer stem cell-like phenotype by up-regulating miR-335 in metastatic breast cancer, in vitro and in vivo
Chen, J. (Creator), Huang, W. (Contributor), Bamodu, O. A. (Contributor), Chang, P. M. (Creator), Chao, T. (Contributor) & Huang, T. (Contributor), Figshare, 2019
DOI: 10.6084/m9.figshare.8341985.v1, https://springernature.figshare.com/articles/Additional_file_1_of_Monospecific_antibody_targeting_of_CDH11_inhibits_epithelial-to-mesenchymal_transition_and_represses_cancer_stem_cell-like_phenotype_by_up-regulating_miR-335_in_metastatic_breast_cancer_in_vitro_and_in_vivo/8341985/1
Dataset
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Monospecific antibody targeting of CDH11 inhibits epithelial-to-mesenchymal transition and represses cancer stem cell-like phenotype by up-regulating miR-335 in metastatic breast cancer, in vitro and in vivo
Chen, J. (Creator), Huang, W. (Contributor), Bamodu, O. A. (Contributor), Chang, P. M. (Creator), Chao, T. (Contributor) & Huang, T. (Contributor), Figshare, 2019
DOI: 10.6084/m9.figshare.c.4558895.v1, https://springernature.figshare.com/collections/Monospecific_antibody_targeting_of_CDH11_inhibits_epithelial-to-mesenchymal_transition_and_represses_cancer_stem_cell-like_phenotype_by_up-regulating_miR-335_in_metastatic_breast_cancer_in_vitro_and_in_vivo/4558895/1
Dataset