2014年6月18日水曜日

乳癌サブタイプを決める遺伝的背景について:Cancer Cell

乳癌サブタイプを決める遺伝的背景について興味深い報告2つ。

Volume 25, Issue 6, 16 June 2014, Pages 748–761

Sumoylation Pathway Is Required to Maintain the Basal Breast Cancer Subtype

  • Summary

  • The TFAP2C/AP-2γ transcription factor regulates luminal breast cancer genes, and loss of TFAP2C induces epithelial-mesenchymal transition. By contrast, the highly homologous family member, TFAP2A, lacks transcriptional activity at luminal gene promoters. A detailed structure-function analysis identified that sumoylation of TFAP2A blocks its ability to induce the expression of luminal genes. Disruption of the sumoylation pathway by knockdown of sumoylation enzymes, mutation of the SUMO-target lysine of TFAP2A, or treatment with sumoylation inhibitors induced a basal-to-luminal transition, which was dependent on TFAP2A. Sumoylation inhibitors cleared the CD44+/hi/CD24−/low cell population characterizing basal cancers and inhibited tumor outgrowth of basal cancer xenografts. These findings establish a critical role for sumoylation in regulating the transcriptional mechanisms that maintain the basal cancer phenotype.





Volume 25, Issue 6, 16 June 2014, Pages 762–777
Article

JARID1B Is a Luminal Lineage-Driving Oncogene in Breast Cancer

  • Summary

  • Recurrent mutations in histone-modifying enzymes imply key roles in tumorigenesis, yet their functional relevance is largely unknown. Here, we show that JARID1B, encoding a histone H3 lysine 4 (H3K4) demethylase, is frequently amplified and overexpressed in luminal breast tumors and a somatic mutation in a basal-like breast cancer results in the gain of unique chromatin binding and luminal expression and splicing patterns. Downregulation of JARID1B in luminal cells induces basal genes expression and growth arrest, which is rescued by TGFβ pathway inhibitors. Integrated JARID1B chromatin binding, H3K4 methylation, and expression profiles suggest a key function for JARID1B in luminal cell-specific expression programs. High luminal JARID1B activity is associated with poor outcome in patients with hormone receptor-positive breast tumors.

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