Report on EMBO Molecular Medicine Conference “Common Mechansims of Mammary Gland Development and Breast Cancer Progression” which took place from 6th – 8th June 2006 at the O’Reilly Hall, University College Dublin, Ireland.
Darran P. O’Connor, Finian Martin and William M. Gallagher
UCD School of Biomolecular and Biomedical Science,
UCD Conway Institute,
University College Dublin,
Belfield, Dublin 4.
Breast cancer is by far the most frequent cancer in women worldwide. On average, 2700 women a year are diagnosed in the island of Ireland with breast cancer, with over 900 dying from this disease and incidence rates for Ireland are increasing by 1.5% per year.
|From left to right: Prof. Finian Martin (Co-Organiser of EMBO Conference, UCD), Dr. Hugh Brady (President, UCD), Prof. Rene Bernards (Netherlands Cancer Institute, Amsterdam and BACR Sponsored Presenter) and Dr. William M. Gallagher (Primary Organiser of EMBO Conference, UCD).
Photograph taken at Iveagh House, St. Stephen’s Green during a reception hosted by the Minister for Health and Children, Ms. Mary Harney, T.D, on 6th July to mark the start of the EMBO Molecular Medicine Conference.
While some success has been achieved in detecting and treating this disease, concerted efforts are still required to refine our understanding of breast cancer progression, with a view to the development of diagnostics and more targeted therapies.
It is becoming clear that cancer cells often share characteristics with those undergoing normal development. Indeed, considerable insights have been gained into the biological basis of breast cancer through the study of how the breast forms and changes during the cycle from birth to puberty to pregnancy. To highlight some of the key advances that have been made in recent years in respect to our understanding of both normal breast development and its dysregulation, investigators at the Conway Institute in UCD (Dr. William Gallagher, Prof. Finian Martin and Dr. Darran O’Connor) organised an international scientific conference from 6th – 8th June 2006 at the O’Reilly Hall, where over 150 delegates from around the world presented their research (www.targetbreast.com).
The conference was primarily supported by EMBO (European Molecular Biology Organization), in addition to the ESF COST B20 action, the Health Research Board of Ireland, Science Foundation Ireland, University College Dublin, the British Association for Cancer Research and Cancer Research Ireland. Over the course of 3 days, mammary gland development, invasion and metastasis, therapeutic implications and future directions, biomarkers and susceptibility genes and “omics” approaches in breast cancer were discussed.
Cell populations must co-ordinate migration, proliferation and apoptosis over space and time to create organised multi-cellular tissues. With regard to breast development, 3-D culture models provide a means to explore potential underlying mechanisms and show how extracellular factors interact with an intrinsic differentiation programme to determine the architecture of breast tissues. During the course of the meeting, delegates heard how 3-D culture models are being used to describe the role of integrin signaling (Charles Streuli, Manchester, UK), changes in the extracellular matrix (ECM), in particular matrix stiffness (Valerie Weaver, Philadelphia, USA) and expression of the Erb2 oncogenic receptor (Senthil Muthuswamy, New York, USA) effect mammary gland development and tissue homeostasis and how, in understanding these key developmental processes, we can improve our search for novel therapeutics to treat malignant disease of the breast.
Breast cancer can spread to almost any region of the body; however, metastases are most frequently found in the bone, lung and liver. Treatment options for advanced metastatic breast cancer are still very limited and this stage of the disease is responsible for the majority of breast cancer deaths. The dissemination and growth of cancer cells in distant organs requires distinct steps, and understanding the basic biology of each step in the process is crucial for the design of therapeutic strategies.
Though large numbers of cancer cells are shed from primary tumours, only a very small proportion of those survive passage through the circulatory system, reach a secondary site and grow to form an overt metastasis. Many of the disseminated cells persist in the secondary organ as dormant solitary cells or micrometastasis. Ann Chambers (Ontario, Canada) showed, through fascinating intravital videomicroscopy, the inefficiency of the metastatic process and the fate of disseminated tumour cells. Improvements in imaging technology allowed the visualisation of these dormant solitary cells, and while their role in cancer progression is still uncertain, they could represent quiescent populations awaiting activation and may also be metabolically active and help prime the micro-environment for incoming tumour cells. Additionally, the role of slug/snail-mediated E-cadherin expression in regulating the epithelial-mesenchymal transition (a hallmark of cancer progression) (Geert Berx, Ghent, Belgium) and the part played by matrix metalloproteases (MMPs) (Barbara Fingleton, Nashville, USA) and intriguing structures called invadopodia (Hideki Yamaguchi, New York, USA) in facilitating the spread of tumour cells were also discussed.
Breast cancer research has also focused in recent years on the search for new biomarkers which accurately diagnose disease, monitor disease status, indicate recurrence, determine metastatic potential and predict therapeutic response. To date, despite the discovery of a whole host of biomarkers, only a handful are routinely used in clinical diagnostics for breast cancer (hormone receptors and HER2-neu being the most common). Delegates heard how technology that has emerged recently has facilitated a high-throughput approach to biomarker discovery and validation, and how tissue microarrays, in particular, would seem to hold the key to translating putative indicators of disease progression from the bench to the bedside (Donal Brennan, Dublin, Ireland).
Targeted therapy results from detailed insights into the processes of tumor initiation and progression. Breast cancer treatment is an excellent model of how these aims can be implemented, for example, the effects of estrogen on mammary gland development and breast cancer growth have been known for many years and the estrogen receptor has long been exploited as a drug target. Endocrine therapies based on estrogen antagonists, e.g. tamoxifen, or more recently, aromatase inhibitors which block the biosynthesis of estrogen, have been of tremendous clinical value (Lesley-Ann Martin, London, UK).
However, even with these impressive advances, there is room for improvement. Rene Bernards (Amsterdam, The Netherlands), introduced the notion of genome-wide RNAi-based screens as a mechanism of gaining insight into the mode of action of small molecules with anti-cancer activity and for detecting genes whose inactivation causes resistance to conventional chemotherapeutic agents, like tamoxifen. The mechanisms which underlie the emergence of resistance of tumor cells to tamoxifen treatment have still to be elucidated, and further insight may also be gained from the detailed analysis of the high molecular weight protein complexes which assemble and disassemble at estrogen receptor-regulated promoter sequences (Frank Gannon, Heidelberg, Germany). These revelations offer many new points of intervention in estrogen-induced gene transcription beyond the conventional disruption of receptor ligand interactions. They also might require “unconventional” drugs, e.g. those that disrupt protein-protein or protein-DNA interactions, and the use of target-specific peptides delivered into cells provides a strategy for reaching this goal (Bernd Groner, Frankfurt, Germany).