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Title: The interplay between MDM2 and PSMA in metastatic breast cancer cells
Author: Bradbury, Robyn
ISNI:       0000 0004 6059 2319
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2016
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Both mouse double minute (MDM2) and prostate-specific membrane antigen (PSMA) are known to be associated with the progressive properties of cancer. Moreover, overexpression of both molecules has been implicated in an increase in the proliferation, migration and invasion of tumour cells. MDM2 is a negative regulator of tumour suppressor of p53 but also is known to play multiple p53-independent roles in many cancer types. PSMA was originally thought to be solely expressed in prostate tissues and overexpression prostatic cancers; however, recently its expression was reported in various other solid tumours, including those of the breast. Our work showed a possible link between these proteins following knockdown of each molecule in breast cancer cell lines, ZR-75.1 and MDA-MB-231, with targeted siRNA molecules. A decrease of MDM2 and PSMA led to a decrease in the proliferative, adhesive, migratory and invasive capacities of the cell lines. Additionally, knockdown of MDM2 and PSMA led to similar changes in secretion of matrix metalloproteinases (MMPs), with decreases in MMP2 and MMP8 being seen from both breast cell lines investigated. It was then seen that a link between the two protein could be mediated through the phosphorylation status of serine 473 on protein kinase B (AKT). PSMA knockdown in both breast cancer cell lines led to a decrease of AKT phosphorylation and thus a decrease in MDM2 serine 188. Additionally, it was found that MDM2 siRNA leads to an increase in c-JUN serine 63 phosphorylation, and that PSMA siRNA can lead to an increase at the same site, depending on the cell line. These results indicate that MDM2, AKT and PSMA may represent a new pathway which could be targeted for therapy for breast tumours and perhaps other types of cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC0254 Neoplasms. Tumors. Oncology (including Cancer)