Identification of Lyn kinase as a therapeutic target for\ud tamoxifen resistant breast cancer

Doctoral thesis English OPEN
Hendley, Rhiannon
  • Subject: RC0254 | RM
    mesheuropmc: skin and connective tissue diseases

Tamoxifen has made a significant contribution in decreasing breast cancer related deaths for over 30 years and until recently was the gold standard for treatment of ER positive breast cancer (Fisher et al, 1998). Resistance to\ud tamoxifen is however a considerable issue with cells utilising a number of molecular mechanisms to bypass the growth inhibition caused by blocking ER activity. This move towards an anti-hormone resistant state from an antihormone\ud responsive state is associated with the transition to a much more aggressive phenotype including increased proliferation and also invasiveness.\ud Thus unfortunately, acquisition of tamoxifen resistance is not only associated with a recurrence of breast cancer, but this cancer is also much more aggressive in nature with fewer treatment options available than the initial\ud cancer.\ud This study has identified Lyn kinase as increased in tamoxifen resistant breast cancer cells compared to oestrogen-responsive breast cancer cells. Subsequent\ud removal of Lyn kinase from tamoxifen resistant breast cancer cell lines using RNAi technology led to a significant decrease in cell proliferation, increased\ud apoptosis and also a decrease in migration and invasion. A mechanism has been suggested whereby Lyn kinase is involved in a calcium dependent zinc wave which ultimately leads to the activation of tyrosine kinases.\ud Metastasis to other sites in the body is ultimately responsible for fatalities due to breast cancer and so being able to block its action is key to treating breast\ud cancer in the clinic. Therefore identifying Lyn kinase as a gene target that leads to the advancement of breast cancer to a more aggressive state provides a powerful tool for treating breast cancer in the clinic.
  • References (3)

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    King, JC. (2011). “Zinc: an essential but elusive nutrient”. Am J Clin Nutr 94(suppl):679S-84S

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