Current Research Interests

(1) Signal integration at the cellular level and its implications in breast cancer:

Steroid receptors such as the estrogen receptors are intracellular soluble receptors. Their activities as transcription factors are regulated by ligand binding. In addition to being regulated by their cognate ligands, for example estrogen in the case of the estrogen receptors, they also integrate other extracellular and intracellular signals. The estrogen receptors are particularly promiscuous. They can be activated by a wide spectrum of direct ligands and factors that act through other signaling pathways.

Since estrogens stimulate the proliferation of a large proportion of breast cancers that express the estrogen receptor α (ER), endocrine therapy aims to block the production of estrogens or access of estrogens to the receptor. However, signaling crosstalk can lead to the activation of ER even in the absence of estrogens or in the presence of the commonly used anti-estrogen tamoxifen.

Our goals are to understand: (i) the molecular mechanisms of signal transduction by ER and its crosstalk with other intra- and extracellular signals; (ii) the genomics of signaling crosstalk; (iii) what factors contribute to rendering the ER tamoxifen-resistant; (iv) the physiological and pathological implications of these mechanisms, notably for breast cancer progression and resistance to tamoxifen; (v) the regulation of ER levels (and those of other nuclear receptors) by miRNAs..

(2) Molecular matchmakers: The Hsp90 chaperone machine

Cellular "matchmakers" such as the molecular chaperone heat-shock protein 90 (Hsp90) and its partner proteins are required for a multitude of cellular processes. As a complex molecular machine they assist a subset of proteins during posttranslational folding, and in some cases they even play a regulatory role.

We are particularly interested in determining (i) the in vivo functions of the Hsp90 molecular chaperone complex both in yeast and in mammals; (ii) the functions of Hsp90α and Hsp90β, of the co-chaperones p23, Cyp40, Aha1 and Aha2, and of Trap1 (the mitochondrial Hsp90 isoform) genes in the mouse and in cells using genetics; (iii) the Hsp90 and Aha1 interactomes. Moreover, we are using virtual screening (computational chemistry) and real screening of chemicals using yeast as a living test tube to identify drugs that are specific for Hsp90 from unicellular pathogens (such as the one causing malaria) and/or specific for one of the two human Hsp90 isoforms.

03/2011