Fondation MEDIC

www.fondation-medic.ch

Molecular and pharmacological investigation of the factors contributing to tamoxifen resistance of ERα-positive breast cancers
[06.08.2013]
Project leader – Didier Picard
Didier Picard

Didier Picard is a full professor at the University of Geneva in the Department of Cell Biology. He studied biology at the University of Zurich, before doing a PhD with prof. Walter Schaffner at the same institution. He then joined the group of prof. Keith R. Yamamoto at the University of California, San Francisco, as a postdoctoral fellow. This is where he started to work on steroid receptors, a subject that he further developed and widened upon starting his own laboratory in Geneva in 1990.

Département de Biologie Cellulaire
Université de Genève, Sciences III
30, quai Ernest-Ansermet
CH-1211 Geneva 4

E-Mail: didier.picard@unige.ch
Lab web page: http://www.picard.ch

Group members
 

Lila Bernasconi

technician

Diana Wider

technician

Pablo Echeverría PhD

postdoctoral fellow

Marta Madon-Simon PhD

postdoctoral fellow

Grégory Segala PhD

postdoctoral fellow

Marcela Bennesch

graduate student

Evangelia Vartholomaiou

graduate student

Melissa Berto

graduate student

Tai Wang

graduate student

Project description
 

Summary

About 70% of all breast cancers are positive for the estrogen receptor α (ERα). ERα is a transcription factor that is activated by the steroid hormone estrogen and then regulates the expression of a panel of genes. In a substantial proportion of breast cancers, active ERα supports excessive growth. This has led to the development of endocrine therapy, which attempts to prevent the activation of ERα with anti-estrogens such as tamoxifen or by blocking the production of estrogens with aromatase inhibitors. Although tamoxifen can be a very effective treatment, one third of the tumors eventually become resistant. While there are probably a vast number of mechanisms that can lead to this resistance, we have characterized one. This involves the activation of ERα by an alternate route. Moreover, mechanisms that we have found to affect the amounts of ERα are likely to have an impact as well. We therefore propose to study these factors as well as to apply state of the art high-throughput technologies to search more comprehensively for novel factors that regulate either the levels of ERα or its activities and to determine systematically whether they play a role in breast cancer and resistance to endocrine therapy.

figure 1

Research focus

We propose to identify and to investigate cellular factors that affect estrogen signaling in a context that is relevant to breast cancer progression and treatment. Breast cancer now affects about one in eight women, and even though substantial progress has been made in early detection, treatment and management, it remains a serious and potentially fatal disease. Since the steroid hormone estrogen promotes the progression of a large proportion of breast cancers by activating the transcription factor "estrogen receptor α" (ERα), anti-estrogens such as tamoxifen are routinely prescribed as a specific adjuvant therapy. Although a relatively straightforward and simple therapy, some tumors are resistant from the outset or resistant variants often arise after years of treatment. Our project aims to achieve a better understanding of the cellular mechanisms that render breast cancer cells resistant to tamoxifen because of altered ERα function.
We have used two complementary biological systems to screen for factors that are required for ERα function.

Comprehensive genome-wide screens for factors required for estrogen-induced activity have been performed both with the budding yeast as a living test tube and by RNA interference in human cells. Some of these screens could be repeated with tamoxifen as well. As soon as we will have prioritized the preliminary hits from these screens, the most interesting subset will be further studied in human cells. The goals of these validation and follow-up experiments for individual candidate factors will be to characterize the molecular mechanisms, to determine their potential role for ERα-associated tamoxifen resistance with breast cancer cell lines and their expression in ERα-positive breast tumor biopsies, and the correlation between their expression and various clinical parameters (ERα and node status, recurrence, endocrine therapy resistance, ....).

In parallel with attempting to identify new/all factors, we will further explore miRNAs that we have found to regulate ERα levels and the components of an ERα complex that we have already found to be involved in tamoxifen resistance. We know that cAMP signaling can lead to tamoxifen-resistant ERα activity by allowing it to recruit the coregulator CARM1 once it has been phosphorylated by protein kinase A. We therefore want to complete our picture of the signaling pathways that lead to this activating phosphorylation and to examine the phosphorylation status of CARM1 in a panel of breast tumor biopsies to evaluate its potential mechanistic and diagnostic importance. Further studies on the other components of this unusual signaling complex, the molecular chaperone Hsp90 and the histone deacetylase 6 (HDAC6), will provide more detailed mechanistic insights and set the stage for fine-tuned diagnostics and for new therapeutic intervention schemes. We anticipate that our cell-based combinatorial drug "treatments" might eventually lead to new clinical trials.

Publications
 
2013 / 10.1073/pnas.1220659110
Yoshida S*, Tsutsumi S*, Mühlebach G*, Sourbier C, Lee M-J, Lee S, Vartholomaiou E, Tatakoro M, Beebe K, Miyajima N, Mohney R, Chen Y, Hasumi H, Fukushima H, Nakamura K, Koga K, Kihara K, Trepel J, Picard D, and Neckers L. The molecular chaperone TRAP1 regulates a metabolic switch between OXPHOS and aerobic glycolysis. Proc. Natl. Acad. Sci. USA 110, E1604-1612
» PubMed
2011
Echeverría PC, Bernthaler A, Dupuis P, Mayer B, and Picard D. An interaction network predicted from public data as a discovery tool: application to the Hsp90 molecular chaperone machine. PLoS ONE 6, e26044
» PubMed
2011 / 10.1371/journal.pone.0016631
Lappano R, Recchia AG, De Francesco EM, Angelone T, Cerra MC, Picard D, Maggiolini M. The cholesterol metabolite 25-hydroxycholesterol activates estrogen receptor α-mediated signaling in cancer cells and in cardiomyocytes. PLoS One. 2011 Jan 31;6(1):e16631
» PubMed
2010 / 10.1101/gad.568410
Carascossa S, Dudek P, Cenni B, Briand PA, Picard D. CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor alpha by cAMP. Genes Dev. 2010 Apr 1;24(7):708-19
» PubMed
2010 / 10.1677/JOE-09-0242
Maggiolini M, Picard D. The unfolding stories of GPR30, a new membrane-bound estrogen receptor. J Endocrinol. 2010 Feb;204(2):105-14
» PubMed
2010 / 10.1016/j.coph.2010.08.009
Pandey DP, Picard D. Multidirectional interplay between nuclear receptors and microRNAs. Curr Opin Pharmacol. 2010 Dec;10(6):637-42
» PubMed
2009 / 10.1038/emboj.2008.304
Pandey DP, Lappano R, Albanito L, Madeo A, Maggiolini M, Picard D. Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF. EMBO J. 2009 Mar 4;28(5):523-32
» PubMed
2009 / 10.1128/MCB.01875-08
Pandey DP, Picard D. miR-22 inhibits estrogen signaling by directly targeting the estrogen receptor alpha mRNA. Mol Cell Biol. 2009 Jul;29(13):3783-90
» PubMed