Rosette Lidereau, PhD

2009-2010 BCRF Project:
During the past two decades, the survival of breast cancer patients has greatly increased due to improvements in screening, early diagnosis and treatment selection. However, around 10% of patients with a diagnosis of early breast cancer will develop distant relapse, an event still deemed as a sign of incurable status despite a very heterogeneous course. Prognosis of this metastatic risk remains a critical issue in daily practice. Of the various prognostic markers available, none give an indication of the risk of metastasis to a specific organ. Such knowledge obtained at first diagnosis would help to plan care for patients, giving information to select new targets for emerging preventive treatments and contributing to avoid overtreatment in specific cases. The aims of this project are the identification and the molecular characterization of genes involved in breast cancer organ-specific metastasis. Such knowledge would help to plan care for patients, giving information to select new targets for emerging preventive treatments and contributing to avoid overtreatment in specific cases.

During the second period of the BCRF grant (February -May 2009), Dr. Lidereau analyzed at the RNA level a collection of up to 600 patients with breast tumors for molecular markers providing an assessment of patients at risk of developing metastases in the bone. In addition, her team evaluated their organ-specific metastasis signatures in the context of breast cancer subtypes. They have started the evaluation of selected "metastasis genes" at the protein level on a large scale basis by the RPPA (Reverse Phase Protein Arrays) technology. They further characterized the most relevant lung metastasis genes (FERMT1 and DSC2) at the functional level. Both genes increased the migratory and invasive properties when overexpressed in breast cancer cell lines. Moreover, FERMT1 was shown to play a key role in the epithelial-mesenchymal transition, a phenotype closely related to the invasive capacities of the cells. Finally, FERMT1 is currently being tested in different laboratory models.

The French researchers recently identified potential prognostic and diagnostic markers for organ-specific metastasis in human breast cancer, using oncogenomic techniques. Their new project aims to validate a small set of prognostic/diagnostic markers whose detection in the primary tumor or in sera, will provide an assessment of patients at risk of developing metastases in the bone, lung, liver and brain. Selected candidate genes will be screened in different cell-based assays (cell adhesion, invasion, migration and proliferation assays) to select those which will be the most potent at affect human breast cancer cell functions in vitro. These genes will next be tested in vivo using models of metastasis. Beside the enhancement of the understanding of the molecular mechanisms underlying the breast cancer metastasis development, this data might provide a potentially valuable tool to allow the clinicians to better define their breast cancer patients with higher risk to suffer from metastases. Finally, such knowledge might raise information to select new targets for emerging preventive treatments and contributing to avoid over-treatment in specific cases.

Mid-Year Progress Report:
Dr. Lidereau and her colleagues have recently identified potential prognostic and diagnostic markers for organ-specific metastasis in human breast cancer, using oncogenomic techniques. Their current project aims to validate a small set of prognostic/diagnostic markers whose detection in the primary tumor or in sera, will provide an assessment of patients at risk of developing breast cancer.

During the period October 2009 -January 2010), they have worked on different aspects of breast cancer metastasis: First, they investigated the molecular portraits of breast tumor metastases according to the intrinsic signature. They found that the breast cancer metastases display specific molecular subtype characteristics with respect to their location. In particular, all lung metastases showed a basal-like profile. So they wanted to assess that their lung metastasis signature was not a surrogate of the basal-like subtype. They analyzed at the RNA level several series of primary tumors already characterized for their subtype status. The researchers showed that their signature is able to distinctly clusterize both the luminal B and basal-like tumors relapsing to the lung (these breast tumors are the main subgroup of tumors relapsing to the lung). This signature is still predictive in these subgroup of tumors. These results have recently been published (Driouch et al., Cancer Res. 2009 Dec 15; 69(24):9507-11).

Second, the researchers continued their analysis at the protein level. They technically validated the concordance of their results, both on cell lines and a series of breast tumors. However, some of the antibodies generated by their laboratory (not commercially available) give rise to unclear RPPA patterns. Therefore, these antibodies have been further purified. They are currently reanalyzing these particular markers. They further pursued the functional characterization of a lung metastasis gene named KIND1. Using a laboratory model of breast tumors in which KIND1 was depleted (by specific ShRNAs), they found that KIND1 facilitates both breast tumorigenicity and lung metastagenicity. In addition of being a potential prognostic marker, this gene also might be considered as a candidate for designing patient-specific therapeutic strategies to prevent or delay the development of lung metastases.

Bio:
Dr. Rosette Lidereau received her PhD (1987) from Paris University, France. Since 1992 she has been a Research Director of the INSERM (Institut National des Sciences et de la Recherche Médicale) and since 2000, she has been in charge of the head of the INSERM Unit 735, located in the Institut Curie / Hôpital René Huguenin (IC/HRH), Saint-Cloud, France. IC/HRH is a non-profit institution dedicated to cancer with a history of medical and biological expertise in breast cancer.

Dr. Lidereau has developed her scientific career on biology of breast cancer within the IC/HRH. Her former research interests are the evaluation of oncogenes' implication in breast tumorigenesis and their impact in clinics as prognostic and predictive factors in breast cancer. She is also the leader of the department of Oncogenetics in the IC/HRH and contributes to the clinics through diagnostics of cancer susceptibility genes mutations.