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Abstract 411: Targeted PF1, JARID1B inhibition induces epigenetic reprogramming in triple negative breast cancer.

Christova, Rossitza, Petrie, Kevin, Bansal, Nidhi, Leibovitch, Boris, Howell, Louise, Gil, Veronica, Zhou, Ming-Ming, Ariztia, Edgardo, Farias, Eduardo, Zelent, Arthur and Waxman, Samuel (2014) Abstract 411: Targeted PF1, JARID1B inhibition induces epigenetic reprogramming in triple negative breast cancer. Cancer Research, 74 (19_Sup). p. 411. ISSN 0008-5472

Item Type: Article

Abstract

Triple Negative Breast cancer (TNBC) is an aggressive subtype of breast cancer associated with early recurrence and poor prognosis. The treatment options are limited due to lack of expression of common drug targets: estrogen receptor (ER), Progesterone receptor (PR) and Epidermal growth factor receptor 2 (Her2). Epigenetic programs can generate aberrant transcription contributing to TNBC progression; however the dynamic and reversible nature of epigenetic changes offers the possibility to reprogram cancer cells to re-express targets that can render TNBC sensitive to targeted therapies like tamoxifen. Envisioning such ‘epidrugs’, we previously published that targeting PAH2 domain of the master transcriptional scaffold Sin3 by stable expression of 13-mer peptide corresponding to a specific motif called SID (mSin3A interaction domain) disrupts its interaction with a small group of SID-containing transcription factors. This interference reverts the expression of important breast cancer-associated genes and impairs tumor growth in vivo. We have now extended our study towards the evaluation of a cell penetrating SID peptide (pSID) in in vitro and in vivo models to establish parameters for the design of targeted epigenetic therapy for TNBC. pSID co-localizes with Sin3A and interference with PAH2-mediated Sin3A functions by pSID is shown by disruption of Sin3A-MAD1 interactions in Co-IP and Duo-Link assays. pSID treatment in MDA-MB 231 cells results in functional re-expression of CDH1 and ER along with increased H3K4 and decreased H3K27 methylation on their promoters. We also show reduction in the tumorsphere formation by pSID-pretreated MDA-MB-231 cells indicating possible epigenetic reprogramming of tumor initiating stem cells towards a differentiated phenotype. Support to this hypothesis is added by the 50% reduction in tumor growth and re-expression of CDH1 observed in FVB mice injected with pSID-pretreated MMTV-myc cells. Moreover, microarray expression analysis indicates pSID-induced EMT reversal, increased cell adhesion and reduced cell migration. Intriguingly, upon further dissection of the mechanism of epigenetic regulation by pSID we show dissociation of two important chromatin readers/modifiers from the Sin3 complex: histone H3K4Me3/2 demethylase JARID1B and H3K4Me0 binding PHD-like domain containing protein PF1; both with significantly correlated overexpression in invasive breast carcinoma. We also observe loss of recruitment of JARID1B but not Sin3A from the CDH1 promoter. Currently studies are underway to understand the cooperative role between JARID1B and PF1 in potentiating the aberrant transcription regulation by Sin3 at important breast cancer-associated promoters that can be selectively reprogrammed by SID decoys. We believe this selectivity can limit the otherwise adverse affects that may be observed by the use of generic HDAC inhibitors and demethylating agents.

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More Information

Depositing User: Kevin Petrie

Identifiers

Item ID: 15822
Identification Number: https://doi.org/10.1158/1538-7445.am2014-411
ISSN: 0008-5472
URI: http://sure.sunderland.ac.uk/id/eprint/15822
Official URL: http://dx.doi.org/10.1158/1538-7445.am2014-411

Users with ORCIDS

ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

Catalogue record

Date Deposited: 22 Mar 2023 15:47
Last Modified: 22 Mar 2023 15:47

Contributors

Author: Kevin Petrie ORCID iD
Author: Rossitza Christova
Author: Nidhi Bansal
Author: Boris Leibovitch
Author: Louise Howell
Author: Veronica Gil
Author: Ming-Ming Zhou
Author: Edgardo Ariztia
Author: Eduardo Farias
Author: Arthur Zelent
Author: Samuel Waxman

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine

Subjects

Sciences > Biomedical Sciences
Sciences

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