Overview
Altered nuclear architecture, as determined by histochemical staining, is a key feature used in the diagnosis of breast cancer by pathologists. Altered nuclear size, and the apparent “texture” of the chromatin are major determinants of the tumour grade that is assigned. However, analysis of these parameters is subjective and does not take into account recent advances in the molecular understanding of how the human genome is organised within the nucleus. For example, we have determined that the chromatin at some sites in the human genome in normal cells is less compacted than at other regions and we have suggested that this is part of a mechanism that controls how and when genes are expressed.
Research aims
Using fluorescence in situ hybridisation, we intend to measure and compare the following features of nuclear organisation in biopsies of breast cancers vs. normal breast tissue:
a) The level of compaction of chromatin of different human chromosomes, and at specific regions of the genome that have been shown to be mis-regulated in breast cancer
b) The relative nuclear position of genes that are mis-regulated in breast cancer.
We will also determine whether changes in nuclear organisation, which we detect in this way, correlate with tumour grades as determined by histopathology, and whether there are differences in the nuclear reorganisation in different breast cancer sub-types (e.g. basal vs luminal; ER+ vs ER-).
To determine how chromatin and nuclear organisation are linked to the biology of the cancer cells we will follow changes in the nuclear architecture of breast cancers at presentation and during their response to endocrine therapies.
We hope that our findings will lead to a better understanding of how genes are mis-regulated in cancer through changes in chromatin structure. Our work may also help to provide more sensitive and specific biomarkers for the detection of very early stage cancer, when diagnosis by histopathology is at its most difficult.
