Despite advances breast cancer management, it remains a leading cause of death in women globally. Breast cancer is molecularly heterogeneous with some subtypes that are challenging to therapeutically target. This necessitates identification and validation of novel targets for breast cancer therapy. This study hypothesised that Popeye domain-containing (POPDC) proteins are dysregulated to promote breast malignancy. The study aimed to determine the potential of POPDC proteins as novel targets for inhibiting breast cancer cell migration and proliferation. Western blot and immunofluorescence assays demonstrated that POPDC1 and POPDC2 were significantly suppressed in malignant breast cells relative to non-malignant breast cells. In ductal carcinoma tissues, POPDC1 was significantly suppressed without correlation to clinical progression. In contrast, POPDC2 and POPDC3 were overexpressed in ductal carcinoma tissues and significantly correlated to HER2+ status and high tumour grade. Secondly, cell membrane expression of POPDC1 and POPDC2 were significantly reduced in malignant cells instead shifted to endosomal trafficking vesicles. Thirdly, suppression and gain of function studies showed that POPDC suppression significantly promoted cell migration and proliferation, while gain of POPDC function significantly inhibited cell migration and proliferation. The study also demonstrated that cAMP interacted with POPDC1, regulates POPDC1 expression levels and potentially controls POPDC1-mediated inhibition of cell migration and proliferation in breast cancer. Finally, this study showed for the first time that EGFR negatively regulates POPDC1 expression in breast cancer cells and the overexpression of POPDC1 can reduce EGFR-mediated cell migration and proliferation in breast cancer cells. In conclusion, POPDC protein expression, localisation and functions change in breast cancer. POPDC1 was also identified as a novel therapeutic target for inhibiting breast cancer cell migration and proliferation that could potentially be targeted to inhibit EGFR-driven breast malignancy. The study also demonstrated POPDC2 and POPDC3 are dysregulated in breast cancer, but in a less consistent and more complex manner.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:737947 |
| Date | January 2017 |
| Creators | Amunjela, Johanna Ndamwena |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=235948 |
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