Aaron Chen

Background: Breast cancer (BC) is the most widespread form of cancer and the leading cause of cancer death among women globally.¹ Several risk factors, including age, gender, family history, menstruation patterns, and hysterectomy have been strongly implicated in the incidence of BC.^{1, 2}  BC follows a 0-4 staging system, which varies based upon tumor size, growth rate, and spread; varied treatments are recommended based on the staging.^3-5 The typical progression of treatment for stages 0-III is as follows: preoperative chemotherapy, lumpectomy or mastectomy, and radiotherapy.⁵ Depending on the subtype of BC, stage IV involves a combination of hormone therapy, chemotherapy, and radiotherapy.⁵ Despite the abundance of therapeutic options, mi-RNAs (miRs) offer a promising alternative in cancer treatment.⁶ MiRs are non-coding RNAs that modify post-transcriptional gene expression by targeting the 3’-untranslated region (3’-UTR) of mRNAs.⁶ It is well recognized that altered expression of miRs results in pathogenetically disrupted biological pathways among cancer patients.⁶ MiR-107 plays a regulatory role in the expression of NEDD9, a scaffolding protein involved in driving breast cancer metastasis through the epithelial-mesenchymal transition (EMT).^7-10 The miR-107/NEDD9 axis offers an encouraging therapeutic target for antitumoral and antimetastatic drugs.⁷

Objective(s): In this narrative review, we delved into a regulatory mechanism of NEDD9, a prometastatic protein in BC.

Search Methods: An online search of the PubMed database was conducted from 2019 to 2024 using the following keywords: “breast neoplasm”, “NEDD9”, “epigenetics”, and “MicroRNA”.

Results: NEDD9’s influence as a pro-metastatic protein is strongly associated with the EMT.⁸ EMT is characterized by a transition from normal cell adhesion and polarity in epithelial cells to mesenchymal properties, which include increased mobility and invasion.⁸ EMT results in a repression of E-cadherin, which is an important component of cell-cell adhesion, and increases expression of N-cadherin (decreases cell adhesion and increases motility), vimentin (cytoskeletal rearrangement), and fibronectin (tumor microenvironment).⁸ In an experiment testing NEDD9’s involvement in breast cancer metastasis, MCF-7 (ER+/PR+), MDA-MB-468, and MDA-MB-231 (TNBC) cell lines were analyzed based on their NEDD9 expression.⁷ Lentivirus-mediated overexpression of miR-107 in MCF-7 and MDA-MB-231 cells inhibits NEDD9 expression, whereas interference with miR-107 leads to significant elevation of NEDD9 expression in both cell lines.⁷ To further demonstrate miR-107’s regulatory effect on NEDD9, MCF-7 and MDA-MB-231 cell lines were transfected with an empty plasmid, an interference lentivirus, or an overexpression plasmid. As the expression of miR-107 increased, the expression of NEDD9 was decreased; these findings indicate the involvement of miR-107 in regulating NEDD9 expression in breast cancer cells.⁷ Using an orthotopic mice model, a xenograft of miR-107 overexpressing or miR-107-silenced MDA-MB-231 cells were subcutaneously injected into 40 balb/c mice.⁷ The fluorescence signal intensity was lower in the miR-107-overexpressing cells at the primary site AND at other body parts compared to the empty vector group, indicating potential inhibition of breast cancer metastasis by miR-107 in vivo.⁷ Using a lung metastasis model, there was a significant reduction in the number and area of pulmonary metastatic nodules in the miR-107 overexpression group compared to the empty plasmid groups.⁷

Conclusion: MicroRNA-based therapy is appealing because of miR’s ability to regulate different genes and pathways.⁶ However, the numerous possibilities of molecular targets are difficult to control, leading to unmanageable clinical results.⁶ Thus, much of the current literature surrounding miR-based therapy is limited to preclinical studies.⁶ MiR-107 downregulated NEDD9 expression, implicating an anti-metastatic breast cancer role.⁷ The overexpression of miR-107 demonstrated a direct inhibitory role among the metastasis of breast cancer cells in-vivo.⁷ By altering cell migration and invasion, miR-107 causes a cascading effect that decreases the expression of NEDD9.^7,8 The miR-107/NEDD9 pathway offers an interesting therapeutic target for the prevention of tumor growth and metastasis among patients with breast cancer.⁷

Works Cited:

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