The goal of our research is to understand the hierarchical relationship between cells in breast epithelium in order to gain an insight into the processes that underlie cancer initiation in this tissue. The primary aim, therefore, is to characterise and to understand the regulation of mammary epithelial stem cells since these are likely to be the targets of cancer-initiating events, and may be the underlying tumourigenic cells in breast cancers. We also wish to understand how steroid hormones such as oestrogen regulate this cellular hierarchy since both normal and tumour development is hormone dependent.
Development of the mammary gland involves the formation of collecting ducts and lobules, both of which are bilayered epithelia made up of contractile myo-epithelial and milk-producing luminal cells. One current interest is which of the Notch, Wnt, TGFbeta, EGF pathways and other relevant (eg. cytokines, Prl, GH and ovarian hormones) signalling pathways regulate stem cell self-renewal. We are also exploiting single cell gene expression analyses, functional genomics and proteomics to identify novel pathways that participate in stem cell regulation.
Identification of stem cell self-renewal pathways may be important for future cancer prevention and therapy. An established concept in leukemia as well as in neural and epithelial cancers, including breast cancer, is that only a minority of cells, i.e. the “cancer stem cells”, have the capacity to initiate tumours. Characterising the cancer stem cell and understanding the molecular basis for dysregulated self-renewal is crucial for identification of a) targets for effective therapeutic intervention, and b) disseminated cells in micrometastases which can initiate tumours.
A second theme in the lab is breast cancer prevention. We aim to investigate basic breast biology, identify early changes that occur in normal tissues and perform preclinical studies that will provide the rationale for novel prevention trials.
Overall, our investigations will lead to an increased understanding of the biology of the normal and malignant human breast which, in turn, could lead to the development of new strategies or new targets for prevention of primary and secondary breast cancer.