|Title:||The role of ADAM9 in triple-negative breast cancer progression|
|Advisors:||Chan, Wing Chi Lawrence (HTI)|
|Subject:||Breast -- Cancer -- Treatment|
Hong Kong Polytechnic University -- Dissertations
|Department:||Department of Health Technology and Informatics|
|Pages:||xviii, 150 pages : color illustrations|
Triple-negative breast cancer (TNBC) is a subtype of breast cancer which characterized as lacking hormone receptors (ER and PR) and human epidermal growth factor receptor 2 (HER2) expression. It is known that TNBC normally has more aggressive and poorer prognosis compared with non-TNBC. Meanwhile, patients with TNBC are less benefit from hormone targeted or anti-HER2 treatment. Targeted compounds are developed to against specific molecules in TNBC, such as epidermal growth factor receptor (EGFR) inhibitors (Cetuximab), poly (ADP-ribose) polymerase (PARP) inhibitors and phosphatidylinositol 3-kinase (PI3K) inhibitors. Several compounds have been approved for TNBC clinical trials, while no significant improvement was observed in enrolled TNBC patients in phase 3 trials.
A disintegrin and metalloproteinases (ADAMs) are a group of transmembrane proteins characterized with the subunit of disintegrin and metalloproteinase domains, which could be useful targets in cancer treatment. Currently, twenty-one members are found to belong to this family in humans. Thirteen of them could shed ligands from cell surface to promote biological processes via their functional protease activities. Specifically, ADAM9, as one of 13 ADAM members, is reported to participate in cell-cell crosstalk and extracellular matrix degradation. ADAM9 is firstly transcripted as a precursor (molecular weight 110 kDa). In Golgi, inADAM9 precursor is activated by cleaving the inhibitory pro-domain by the pro-protein convertase furin and becomes the matured form (84 kDa) with functional protease activities followed by translocating to cell membrane. It has been indicated that ADAM9 participates in cancer progression by mediating epithelial-to-mesenchymal transition (EMT), receptor ligands cleavage and signaling pathway stimulation. ADAM9 overexpression was found in several cancers, such as esophageal squamous cell carcinoma, pancreatic cancer, prostate cancer and breast cancer. However, it is still unclear whether ADAM9 is upregulated in TNBC and the role of ADAM9 in TNBC progression.
To investigate the role of ADAM9 in TNBC progression, we detected ADAM9 expression in clinical samples, performed correlation analysis between ADAM9 expression and survival in TNBC patients and knocked down ADAM9 expression in TNBC cell lines by using small interference RNA (siRNA) to observe the change of cancer cell motility and invasive phenotypes. The pathway that ADAM9 involved in TNBC progression is explored by western blotting.
Results and conclusions
We extracted the ADAM9 expression data in TNBC and non-TNBC patients from public database and found that ADAM9 significantly overexpressed in TNBC patients (p-value < 0.01). ADAM9 expression was also upregulated in TNBC cell lines compared with non-TNBC cell lines. Being consistent with these results, TNBC specimens (n = 24) collected from a clinical unit showed markedly upregulated ADAM9 expression compared with non-TNBC specimens (n = 20, p-value < 0.05). Survival analysis indicated that upregulated ADAM9 expression was negatively associated with survival rate of breast cancer patients. Using siRNA to knockdown ADAM9 expression in TNBC cell lines (MDA-MB-231 and Hs578t) inhibited the growth, migration and invasion of TNBC cancer cells. Furthermore, western blotting results indicated that ADAM9 mediates TNBC progression via AKT/NF-kB Pathway. In general, our findings indicated that ADAM9 was overexpressed in TNBC cells and patients when compared with non-TNBC. Increased ADAM9 expression is associated with poorer survival in patients with TNBC. ADAM9 overexpression promoted the cell proliferation, migration, and invasion in TNBC cells by activating the AKT/NF-kB pathway.
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