Polycomb Genes and Large Non Coding RNAs Expressions in Invasive Breast Carcinomas: New Clues for Epigenetic Targeted Therapies
Didier Meseure, Kinan Drak Alsibai, Martine Trassard, Rosette Lidereau, Ivan Bieche. Institut Curie, St Cloud, France
Background: Epigenetic deregulation and carcinogenesis are intimately connected and gene silencing is a major consequence of epigenetic modifications in cancer cells. Polycomb group proteins (PcG) play important roles by inhibiting chromatin remodeling and transcription, silencing tumor suppressor genes, regulating stem cells and interconnecting with Wnt/beta-catenin, TGF-beta and Sonic-Hedgehog pathways. There are at least two complexes: PRC1 (CBX7/8, HPC, Bim1, RING) and PCR2 (EZH2, EED, SUZ12, Jarid). Histone methyltransferase EZH2 and CBX7 act as transcriptional repressors of many genes and are particularly implicated in silencing of the INK4b/ARF/INK4a locus.
Design: By using real time RT-PCR in a series of 80 IBCs, we quantified mRNA expression levels of ANRIL, HOTAIR, EZH2, SUZ12, CBX7, Bmi1, HMGA1, RUNX3, HDAC2, TWIST1, VIM, P16, P15 and P14/ARF genes. Immunohistochemistry (IHC) in a series of 70 IBCs and a retrospective RNA series of 453 well-characterized tumors were used to confirm results and establish statistical correlations.
Results: RT-PCR revealed high mRNA levels of ANRIL, HOTAIR, EZH2, SUZ12 and Bmi1 but an unexpected loss of expression of CBX7. Moreover, underexpression of CBX7 was associated with overexpression of HGMA1, MiR181b, P16, P15, P14/ARF, HDAC2, VIM and TWIST1. IHC showed intense nuclear positivity with anti EZH2 and HMGA1 Abs, variable nuclear and cytoplasmic staining with anti P15 and P16 Abs and no staining with anti CBX7 Abs. Mutual positive correlations were observed between (i) ANRIL, EZH2, SUZ12, P14/ARF, P15, P16 and (ii) CBX7, CDH1, VIM, TWIST1. No correlation was observed between Bim1, TWIST1 and HOTAIR.
Conclusions: Polycomb EZH2/SUZ12/Bim1 and the Large non Coding RNAs ANRIL and HOTAIR are overexpressed in invasive breast carcinomas. Loss of expression of CBX7 might be explained by HMGA1/MiR181b overexpression, is associated with P14/ARF, P15 and P16 overexpressions. CBX7 seems to have oncosuppressive properties in IBCs and its underexpression is correlated with a more aggressive phenotype, partially via down-regulation of E-cadherin expression.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 54, Wednesday Morning