Lyn kinase in Basal breast cancers

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Copyright: Porta Cubas, Ana
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Abstract
Breast cancer is extremely heterogeneous, to the extent that some consider it to be composed of distinct diseases. Over the last 10 years, research has driven a new classification of Breast cancers, based on the expression of different molecular markers. This newer system is able to divide Breast cancers into at least 5 different subgroups. One subgroup, the ‘Basal breast cancers’ is of particular concern due to its younger age at diagnosis, increased aggressiveness, shorter survival and lack of targeted therapies. Studies have found that cell lines representing this subtype are sensitive to the multikinase inhibitor ‘Dasatinib’. This suggests that kinase/s targeted by Dasatinib may be overexpressed or deregulated in Basal breast cancers, and may thus represent novel therapeutic targets. To investigate this hypothesis, mRNA and protein expression of some of the known Dasatinib kinase targets was compared between cell lines representing Basal breast cancer and the less aggressive Luminal breast cancer. One candidate kinase, Lyn, was significantly overexpressed at the mRNA and protein level in Basal versus Luminal breast cancer lines, and exhibited increased activity in the Basal subgroup. To investigate the mechanisms regulating Lyn activation, cell lines were stimulated with candidate growth factors. HGF stimulated Lyn activity in one cell line suggesting that Lyn forms part of the Met signalling pathway. However, Lyn knock down did not affect the activity or total levels of signalling proteins comprising the Met pathway, nor did it affect HGF-induced cell scattering. Interestingly, Lyn depletion did affect the morphology of cells upon starvation, with cells becoming more dissociated and fibroblastic. Lastly, the translational relevance of these findings was tested by investigating Lyn expression in a Breast cancer patient cohort by immunohistochemical staining. Lyn was found to be significantly overexpressed in the Basal subgroup of patients and strongly associated with it. In addition, Lyn expression was associated with poor prognosis. Thus, while the functional role of Lyn in Basal breast cancer requires further characterisation, it represents a novel biomarker of the Basal breast cancer subgroup and may represent a therapeutic target in Basal breast cancer cells.
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Porta Cubas, Ana
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Publication Year
2011
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Thesis
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Masters Thesis
UNSW Faculty
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