Dual siRNA-miRNA therapy to inhibit tumour invasion and metastasis in breast cancer


Sanmartín Outumuro, Maria

Metastasis is the main cause of morbidity and mortality in breast cancer patients, mainly be-cause of the difficulty of performing a successful surgery and the lack of effective drugs once the metastatic process has started. Existing treatments rely on highly toxic chemotherapeutic drugs and radiotherapy, which present poor survival rates and lead to severe side effects for the patient given the systemic nature of the therapies. Alternatively, RNA therapies such as siRNA and miRNA, offer a potential strategy to target dysregulated key genes in metastatic cancer presenting lower side effects owing to the selective expression of such genes in cancer cells.
Matrix metalloproteinase-9 (MMP-9) is an overexpressed protein in metastatic breast cancer cells responsible for collagen type IV degradation, one of the main components of the extra-cellular matrix (ECM). miR-9 is a type of microRNA that has also been reported to be upreg-ulated in breast cancer and has as a direct target the adhesion protein E-cadherin, which is known for its tumour-suppression nature.
In this study, a highly selective therapy consisting of MMP-9 targeting siRNA and anti-miR-9 was administrated to breast cancer cells with the objective of silencing MMP-9 and upregu-lating E-cadherin. The pre-designed siRNA and miRNA were transfected in 4T1 cells with optimised pBAE nanoparticles. MMP-9 was silenced with a concentration of 0.3 μg/well, which slowed down the migration capacity of the cancer cells. However, no differences in E-cadherin expression were observed after the treatment due to an alternative migration model displayed by the 4T1 cell line known as collective migration. E-cadherin is essential in this process since it is the responsible of maintaining cells connected, forming clusters that will later migrate. Due to the migration model of 4T1, the effect of anti-miR-9 treatment and the possible syner-gistic effect with the pre-designed siRNA were inconclusive. A single-cell migration cell line would be more suitable for the therapy designed in this study.



Borrós Gómez, Salvador
Oliva Jorge, Núria


IQS SE - Master’s Degree in Bioengineering