Stromal and epithelial changes in breast cancer following endocrine treatment

UoM administered thesis: Phd

  • Authors:
  • Narges Azadbakht

Abstract

Anti-oestrogens and aromatase inhibitors are currently used as endocrine therapies in breast cancer. Despite the significant role that these treatments play in reducing breast cancer mortality, some patients may display intrinsic and acquired therapeutic resistance. Different mechanisms are thought to contribute to endocrine resistance in patients treated with anti-oestrogens such as tamoxifen and aromatase inhibitors such as letrozole.The importance of epithelial-stromal interactions in progression of breast tumour and the potential contribution of these interactions in resistance to tamoxifen have been suggested using data from different studies. Stromal compartment has also been shown to exhibit possible prognostic and therapeutic significance in breast cancer. Therefore it is essential to acquire better understanding of the changes in stromal and epithelial cells that occur during successful and unsuccessful endocrine treatment.In this study an important trial in which patients received tamoxifen for short windows was under investigation. Biopsies were taken from these patients before and after treatment. These biopsies were available as formalin-fixed paraffin-embedded (FFPE) tissue blocks. Responding and non-responding patients were identified according to the Ki67 scores. Laser Capture Microdissection (LCM) was utilised to microdissect epithelial and stromal cells from the biopsies taken after treatment. The samples obtained following microdissection underwent RNA extraction and were subsequently used for gene expression profiling.Several differentially expressed genes in the epithelial and stromal compartments of tamoxifen responding and non-responding cases were identified. To assess the significance of the differentially expressed genes between the non-responding and responding cases, bioinformatics approaches were employed to incorporate the acquired data into functional enrichment analysis, pathway analysis and network construction. To examine the presence of possible predictive markers for therapeutic response and potential targets for therapy in breast cancer within the differentially expressed genes, data was compared to several published gene sets and publicly available datasets. Several significant genes involved in recognised pathways and networks were identified within the list of differentially expressed genes. The presence of previously proposed possible markers within the differentially expressed genes was also confirmed. These findings can be further explored for the future management of breast cancer.

Details

Original languageEnglish
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Award date31 Dec 2014