Abstract 971: Identification of BCL6 targeted therapies for breast cancer through gene expression networks

Conference Paper


  • Abstract Breast cancer remains a deadly disease for countless women, thus new treatment strategies must be developed. Since inappropriate activation of transcription factors is a common pathogenic event in breast cancer, targeting these proteins may be a tractable new strategy. In particular, we have found that the BCL6 transcriptional modulator is expressed in 11 out of 12 breast cancer cell lines. In addition, BCL6 has been reported to be expressed in the majority of high-grade ductal carcinomas. Importantly, inhibiting BCL6 expression by RNA interference reduced cell survival. We hypothesized that BCL6 target gene expression profiles could be used to identify compounds with BCL6 inhibitory activity. To generate a breast cancer specific BCL6 gene signature, we employed the combination of gene expression microarrays and BCL6 binding sites identified by ChIP-seq in breast cancer cells. These BCL6 target gene profiles were then used to interrogate the Connectivity Map, a compilation of gene expression signatures reflecting the effects of more than 1300 compounds. This allowed us to identify compounds whose gene expression signature was the inverse of that mediated by BCL6, and might thereby function as BCL6 inhibitors. We screened six of these compounds for BCL6 inhibitory activity using a BCL6-specific reporter which identified disulfiram, celastrol, and harmol as inhibitors of the transcriptional repressor effects of BCL6. Importantly, treating breast cancer cells with these compounds reduced the viability of these cells. Moreover, combining these compounds with cytotoxic agents used in breast cancer therapy enhanced cell killing. In addition, combining these agents with a peptidomimetic of BCL6 also enhanced cell killing. Taken together, these studies show that BCL6 is a key therapeutic target in breast cancer, and that gene signature analysis can be used to identify novel inhibitors of this protein that have activity in breast cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 971. doi:1538-7445.AM2012-971
  • Authors

  • Walker, Sarah
  • Cerchietti, Leandro C
  • Nicolais, Maria C
  • Yuan, Guo-Cheng
  • Melnick, Ari
  • Frank, David A
  • Status

    Publication Date

  • April 15, 2012
  • Has Subject Area

    Published In

  • Cancer Research  Journal
  • Digital Object Identifier (doi)

    Start Page

  • 971
  • End Page

  • 971
  • Volume

  • 72
  • Issue

  • 8_Supplement