Awards and Distinctions

• Holder of a Canadian Institutes for Health Research Senior Scientist Award

• Holder of a Medical Research Council of Canada Scientist Award

• Holder of a Medical Research Council of Canada Scholarship

• Holder of a Medical Research Council of Canada Centennial Fellowship

• Holder of a Medical Research Council of Canada Fellowship

• Student Research Award of the Canadian Society for Clinical Investigation

• Student Research Award of the Canadian Society for Clinical Investigation

• Merck Frosst Award for Excellence in Research, Department of Medicine, McGill University

• Holder of an award provided by La Direction Générale de l'Enseignement Supérieur du Québec

• Holder of a Medical Research Council of Canada Studentship

Research interests

Orphan nuclear receptors

Steroids, thyroid hormones and derivatives of vitamin A are small liposoluble molecules that regulate development, differentiation and physiological response to diverse stimuli and are essential to the survival of the individual. The recognition that the steroid, thyroid and retinoid receptors constituted only a small subset of a large number of related gene products is around ten years old. The year 1988 witnessed the identification of the first cDNA clones encoding polypeptides with structural features suggestive of cryptic steroid hormone receptors, and at that time one could identify about a dozen or so distinct nuclear receptor-like proteins. There are now over fifty identified in various species and, mainly through the various genome sequencing projects, the number is now increasing at a rapid pace. Because the discovery of all these putative nuclear receptors has not been anticipated by previous physiological studies and therefore not linked with the biological effects of a particular hormone or ligand, these new gene products were referred to as orphan nuclear receptors. That the activity of orphan nuclear receptors could be potentially regulated by natural ligands led to the tantalizing suggestion that new hormone response systems remained to be discovered. Interest in orphan nuclear receptor research was also stimulated by the knowledge that classic members of the superfamily of nuclear receptors and their ligands play crucial roles in development, homeostasis and diseases. The possibility that nuclear receptors activity might be regulated by the direct action of natural and synthetic compounds makes orphan receptors good targets for drug discovery. Therefore, the existence of a large number of potential new receptors offers the exciting opportunity to develop novel therapeutic agents, even in the absence of known natural ligands, to treat a variety of illnesses, including diabetes and cancer. For these reasons, the study of orphan nuclear functions has regrouped scientists from a wide variety of fields. Our own studies concentrate on finding physiological functions and ligands for members of the ERR (estrogen receptor-related receptors) and ROR (retinoid receptor-related orphan receptor) families using a combination of molecular, cellular and in vivo assays.

Vitamin A signaling

The research endeavors of my laboratory are also directed toward understanding the molecular basis of vitamin A action. Vitamin A and its biologically active derivative retinoic acid (RA) are essential for the health and survival of the individual. These natural compounds, together with a large repertoire of synthetic analogs, are referred to as retinoids. It is now well known that retinoids can suppress carcinogenesis and metastasis. Transformed cells can be induced to undergo differentiation in response to retinoids and these compounds have been tested as chemopreventive agents and used clinically in the treatment of a variety of cancer including melanoma, head and neck tumors and promyelocytic leukemia. Vitamin A deficiency, which has been demonstrated to be functionally equivalent to the loss of retinoid receptor gene(s), is also associated with increased incidence of certain cancers in human. Therefore, the possibility that retinoid receptor genes might be genetically mutated in tumor cells has received considerable interest in the last five years. Our research is directed at generating genetically altered mouse strains to study the role of retinoid receptors in cancer progression. These studies should improve our basic knowledge of retinoid physiology and lead to a better understanding of the role of retinoids in suppressing the development of neoplastic cells.

Role of estrogen receptors in breast cancer

Perhaps one of the most exciting long-term hopes in breast cancer treatment is that a better understanding of the role of hormones in mammary differentiation, such as that which occurs during mammary gland development and potentially protects against breast cancer, will lead to new effective strategies in breast cancer prevention and treatment. Thus, our research is directed at improving our knowledge of the roles of estradiol, an ovarian hormone that is implicated in the growth and proliferation of normal and abnormal mammary cells. Using a gene targeting approach, our current objectives are to study the signaling pathways implicated in the activation of its two receptors (alpha and beta) during mammary gland development.

Estrogen receptors can be activated by two main pathways, directly by estradiol or through phosphorylation of its amino-terminal domain by the mitogen activated protein kinase (MAPK). Understanding the role played by each signaling pathways at different stages of mammary gland development is likely to have a dramatic impact on the design of future endocrine-based therapies. In addition, the generation of novel animal models with impaired receptor functions may help in the development of new screening strategies necessary for the search for more potent and specific anticancer agents.

Functional genomics of breast cancer

This is a novel team-oriented effort (led by Dr. Morag Park, Molecular Oncology Group) directed at the identification and characterization of new targets for the development of future therapeutic strategies. Breast cancer is the second leading cause of cancer related deaths in women in Canada. Human cancer, including breast cancer, is caused by a complex combination of the genetic makeup of each individual and genetic lesions that accumulate and evolve over a period of many years in somatic cells. These changes are manifested by the dysregulation of the expression of specific genes, some of which play a causal role in the disease and others are as a consequence of the unique characteristic of the tumor cells. The identification of genes whose expression is idiosyncratic to human breast cancer has been a primary goal to identify potential targets for therapy and to discover new prognostic indicators. However, despite significant efforts in the delineation of the molecular profile of breast cancers, tumor size and lymph node status still remain as the most sensitive prognostic markers. To have an impact on patient survival from this disease in the future, it is imperative that sensitive markers and predictors of response to currently available chemotherapeutic agents and key targets for which to design better and more accurate therapeutics be identified.

Previous approaches have been limited to scalability and sensitivity of detection of differential gene expression in cancerous versus normal tissue. Over the past five years there has been an explosion of sequence information from the human genome sequencing program. Databases now comprise over 500,000 pieces of both known and uncharacterized genes and technologies have been developed that allow one to establish the expression profile of these genes in any given tissue using microarray technology. This technology is established within the MUHC and McGill University. We have begun to use these technologies in two ways: first, to generate the molecular profile of human breast cancers as the disease progresses and eventually to use this information to tailor individual therapeutic strategies; second, to identify and characterized novel genes whose mys-expression contribute to the development and progression of breast tumors.

Conclusion

It is hoped that our molecular and genetic analysis of orphan nuclear receptors, retinoid action and estrogen receptors will lead to an increase in our understanding of these hormone-based systems which, in turn, will help develop more efficient therapy for treatment of cancer.

Selected Publications

2006
Blanchette, M. et al. Genome Research (in press).
Genome-wide computational prediction of transcriptional regulatory modules reveals new insights into human gene expression.

2006
Grégoire, S. et al.J. Biol. Chem. 281:4423-4433
Control of MEF2 transcriptional activity by coordinated phosphorylation and sumoylation.

2005
Wende, A. R. et al. Mol. Cell. Biol. 25:10684-10694.
PGC-1α coactivates PDK4 gene expression via the orphan nuclear receptor ERRα: a mechanism for transcriptional control of muscle glucose metabolism.

2001
Tremblay G.B. et al. Genes & Dev 15:833
Discovery of the first ligand for the ERR orphan nuclear receptors. This discovery linked estrogen pharmacology to a group of orphan nuclear receptors.

1999
Tremblay A. et al., Molecular Cell 3:513
First demonstration that phosphorylation of a nuclear receptor may lead to the recruitment of coactivator proteins.

1997
Luo J. et al. Nature 388:778
Genetic ablation of the mouse ERRβ gene showed for the first time that the chorion modulates trophoblast cells proliferation during placentation.