MDGI, MIG-6 and EIG-121 Are Negative Regulators in EGFR Trafficking and Potential Biomarkers to EGFR Inhibitor Therapy in Triple-Negative Breast Carcinomas.
Didier Meseure, Sophie Vacher, Kinan Drak Alsibai, Martine Trassard, Florence Lerebours, Jean Marc Guinebretiere, Rosette Lidereau, Ivan Bieche. Institut Curie, Hopital Rene Huguenin, St Cloud, France
Background: Understanding complexity of EGFR regulation mechanisms and molecular basis of resistance to EGFR inhibitors is crucial. EGFR targeted therapies are actually performed in triple negative breast carcinomas (TNBC), without identified activating EGFR gene alteration and with a still controversial EGFR expression status. In order to identify new targeted modalities, we explored three post traductional EGFR trafficking molecules: MIG-6 (Mitogen-Induced Gene-6), EIG-121 (Estrogen-Induced Gene-121) and MDGI (Mammary-Derived Growth Inhibitor). MDGI induces intra-cellular accumulation of EGFR. MIG-6 and EIG-121 specifically link EGFR with (i) the SNARE protein STX8 (MIG-6) or (ii) the autophagosome marker LC3 (EIG-121) and are implicated in a tumor suppression mechanism through recruitment of internalized receptors to late endosomes, lysosomal degradation and autophagy.
Design: EGFR, MDGI, EIG-121 and MIG-6 mRNA level expressions were investigated by real-time quantitative RT-PCR in a series of 471 breast carcinomas (BC). BC were subdivised into 4 sub-groups according to RH (ERa and PR) and HER2 status: PPP (ER+, PR+, HER2+; n=56), PPN (ER+, PR+, HER2-; n=296), NNP (ER-, PR-, HER2+; n=48) and NNN (ER-, PR-, HER2-; n=71). Immunohistochal assays (IHC) were performed in a series of 88 BC using a panel of anti-EGFR, EIG-121, MIG-6 and MDGI antibodies (Abs). Immunostaining was assessed using intensity score (0 to 4+).
Results: In the TNBC subgroup, RT-PCR identified low expression levels of EGFR (global: 84.6%, NNN: 63.5%, NNP: 69.6%, PPN: 91.5%, PPP: 88%), MDGI (global: 25.7%, NNN: 33.3%, NNP: 23.9%, PPN: 26%, PPP: 16%), EIG121 global: 16.1%, NNN: 60.3%, NNP: 13%, PPN: 7.5%, PPP: 12%) and MIG-6 (global: 25.7%, NNN: 28.6%, NNP: 32.6%, PPN: 51.2%, PPP: 42%). Protein underexpression was also confirmed in TNBC by IHC for EGFR (59%), MDGI (36%), EIG-121 (65%) and MIG-6 (31%). A statistically positive correlation was observed between EGFR, MDGI, EIG-121 and MIG-6 RNA levels and protein expression status (Kruskall Wallis's H test; P<10-5).
Conclusions: Underexpression of the three EGFR post-traductional negative regulators MDGI, EIG-121 and MIG-6 can potentially create an aberrant EGFR-mediated oncogenic signaling pathway in BC. In the TNBC subgroup, MDGI, MIG-6 and EIG-121 might be particularly useful biomarkers in targeted EGFR therapy when EGFR expression level is normal to high and/or MDGI, EIG121 and MIG-6 expression levels are low.
Wednesday, March 2, 2011 1:00 PM
Poster Session VI # 3, Wednesday Afternoon