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Title: Functional evaluation of members of the LIV-1 family of proteins and their role in breast cancer
Author: Normawati, Mohamad Zahari
ISNI:       0000 0004 2747 3609
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2008
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All nine members of the LZT subfamily have similarities to members of the ZIP superfamily, especially in the region associated with their ability to transport zinc intracellular. Computer analysis of the nine sequences suggests that they are all members of this subfamily, however, in phylogenetic tree some members group separately, suggesting differences in function. The LZT-Hs7, LZT-Hs8 and LZT-Hs9 were cloned into a vector suitable for expression of recombinant proteins in mammalian cells. For the first time, this demonstration showed, a plasma membrane location for LZT-Hs7 and LZT-Hs8 which similar finding to LIV-1, and an intracellular location for LZT-Hs9, similar to that observed previously for LZT-Hsl. In addition, zinc transport capability was investigated. Affymetrix U133A analysis of LZT-Hsl, LIV-1, LZT-Hs4, LZT-Hs5 and pS2 confirmed that LZT-Hsl, LIV-1 and LZT-Hs4 were regulated by estradiol. This study was extended to investigate the expression of all nine family members in breast cancer cells treated with oestradiol, anti- oestrogens and additionally in tamoxifen and faslodex resistant cells, using semi-quantitative PCR. Differential expression of these family members was seen with some members constitutively expressed whilst others either elevated or reduced in the different conditions. This analysis demonstrated that LZT-Hsl was considerably elevated in tamoxifen resistance. In an effort to investigate a possible role for LZT-Hsl in tamoxifen resistant cells, it was reduced by siRNA. Interestingly, in the presence of siRNA for LZT-Hsl, it was not possible to demonstrate the activation of EGFR or Src as previously observered in the tamoxifen resistant phenotype using Western blotting analysis. This is an exciting result, which suggests a role for LZT-Hsl in driving the growth of tamoxifen resistant breast cancer cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available