Senior Lecturer and Breast Cancer Campaign Fellow

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. The secondary aim is to understand how steroid hormones such as oestrogen regulate this hierarchy since both normal and tumour development is hormone dependent.

Since mammary development and breast tumourigenesis are promoted by the ovarian steroids oestrogen and progesterone, we are concerned with the mechanisms by which these hormones control stem cells and proliferative progeny in normal breast tissue. We were the first to demonstrate that steroid receptors are limited to a non-proliferative sub-population, often found adjacent to dividing cells, and that they may therefore control proliferation via paracrine factors (Clarke et al., 1997).

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, Hedgehog, Wnt, TGFbeta, EGF pathways and other relevant (eg. Prl, GH and ovarian hormones) signalling pathways regulate stem cell self-renewal. We are also exploiting gene expression arrays, methods for 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 emerging concept is that in leukemia as well as in neural and epithelial cancers, including breast cancer, 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) those cells in micrometastases which can initiate tumours.

A second theme in the lab is identifying early changes that occur in normal and premalignant tissues and predict the emergence of a tumour. If these changes can be detected and prevented, then it may be possible to reduce the increasing incidence of breast cancer, particularly in the developed Western countries where the lifetime risk of breast cancer now exceeds one in ten women.
The results of these investigations should lead to an increased understanding of the biology of the normal human breast which, in turn, could lead to the development of new strategies or new targets for breast cancer prevention and therapy.

Links:

Manchester Breast Centre Website: http://www.mcrc.manchester.ac.uk/mbc/

University of Manchester Stem Cell Network Website: http://www.ls.manchester.ac.uk/research/themes/stemcellresearch/

Latest Publications:

Harrison H, Farnie G, Howell SJ, Rock RE, Stylianou S, Brennan KR, Bundred NJ and Clarke RB (2010) Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor, Cancer Res, 70, 709-18.

Ong KR, Sims AH, Harvie M, Chapman M, Dunn WB, Broadhurst D, Goodacre R, Wilson M, Thomas N, Clarke RB* and Howell A* (2009) Biomarkers of dietary energy restriction in women at increased risk of breast cancer. Cancer Prevention Research, 2(8), 720-731. *Co-corresponding authors.

I did my undergraduate BSc studies in Biology at the University of Sussex and the Université de Grenoble in France, graduating in 1987.

Following two and half years as a Research Assistant with Professor Potten at the Paterson Institute for Cancer Research, I studied the control of proliferation in the normal and neoplastic human mammary gland for my PhD at The University of Manchester (1995). Subsequently, I undertook post-doctoral training with Dr Liz Anderson in the Clinical Research Department of The Christie, Manchester.

I returned to The University of Manchester as a Cancer Research UK Research Fellow in 2001, becoming a Group Leader in the Division of Cancer Studies at the Paterson Institute for Cancer Research.

I am currently Senior Lecturer and Breast Cancer Campaign Research Fellow in the School of Cancer, Enabling Sciences and Technology in the Paterson Institute for Cancer Research, University of Manchester. 

BSc (Hons), PhD

Lab staff

Gillian Farnie, PhD - Breast Cancer Campaign Research Fellow

Rognvald Blance, MSc - Breast Cancer Campaign Scientific Officer

Kath Spence, BSc - Genesis Scientific Officer

Pam Willan, MRes - Breast Cancer Campaign Research Assistant

Ciara O'Brien BSc, MRCP - Cancer Research UK-funded Clinical Research Fellow

Matt Ablett, MRes -BBSRC CASE-funded PhD Student

Andre Vieira, MSc - FCT (Portuguese govt.)-funded PhD Student (3 month visit)