Abstract P4-05-04: MECP2 is a frequently amplified oncogene and potential therapeutic target in TNBC
Authors: Daniel P Silver, Manish Neupane, Allison P Clark, Marc Vidal, David E Hill
Journal: Cancer Research (2015)

Abstract Background: To identify new oncogenes that drive cancer development, we conducted an unbiased genome-scale screen for genes that can substitute for activated RAS in oncogenic transformation. We focused attention on one of the new potential oncogenes identified in this screen, Methyl CpG Binding Protein 2 (MECP2), which has no previously described role in malignancy and is amplified across ∼20% of all human cancers, and ∼30% of Triple-Negative Breast Cancer (TNBC). MECP2 is an X-linked gene known to bind methylated cytosines, and can act as a transcriptional repressor in this context. Recent studies show that it also acts as a transcriptional activator, likely through binding to another epigenetic modification of DNA, 5-hydroxymethylcytosine (5hmC). Results: MECP2 is as potent as activated RAS in conferring anchorage independent growth upon primary human mammary epithelial cells (hMECs) previously transduced with the SV40 early region and hTERT (N−RAS hMECs). MECP2 partially rescues the growth inhibition of RAS-addicted human cancer cell lines after the shRNA-mediated suppression of RAS. MECP2 expresses two spliced isoforms; experiments showed the short isoform activates the MAPK pathway, while the long isoform activates the PI3K pathway. Neither isoform alone can cause growth of N−RAS hMECs as a xenograft in nude mice; together, they can. The transformation and growth factor pathway induction activities of MECP2 absolutely require its DNA-binding activity. A number of TNBC cell lines have amplified, overexpressed MECP2, and of the first 13 TNBC patient-derived xenografts examined, 4 have MECP2 overexpression. Several TNBC cell lines that have amplified, overexpressed MECP2 show significant growth inhibition after shRNA-mediated downregulation of MECP2 (MECP2 addiction), while a breast cancer cell line without MECP2 overexpression showed no such inhibition. N−RAS hMECs transformed with MECP2 are an order of magnitude more sensitive to either of the DNA methylation inhibitors 5-azacytidine or decitabine than isogenic cells transformed by activated RAS, or isogenic cells without an additional transforming gene. Further, we find that combined treatment with the DNA methylation inhibitor 5-azacytidine and the HDAC inhibitor Trichostatin A is synergistic in our hMEC experimental system. Conclusion: MECP2 is a commonly amplified and overexpressed oncogene whose two splicing isoforms together recapitulate the major oncogenic functions of activated RAS. Because MECP2 requires DNA binding to methylated or hydroxymethylated cytosines for its tumor-promoting activities, DNA methylation inhibition with FDA-approved drugs may be therapeutic for tumors overexpressing MECP2. Citation Format: Daniel P Silver, Manish Neupane, Allison P Clark, Marc Vidal, David E Hill. MECP2 is a frequently amplified oncogene and potential therapeutic target in TNBC [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-05-04.