Abstract P1-05-24: Pharmacologic reversion of epigenetic silencing of the PRKD1 promoter blocks breast tumor cell invasion and metastasis

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 24_Supplement; pp. P1 - P1-05-24
• Main Authors: Borges, S, Doppler, H, Andorfer, CA, Perez, EA, Sun, Z, Anastasiadis, PZ, Thompson, AE, Geiger, XJ, Storz, P
• Format: Journal Article
• Language: English
• Published: 15.12.2012
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.SABCS12-P1-05-24

Abstract Epigenetic silencing of tumor suppressing genes by promoter-specific DNA methylation is common in many types of cancer. As an early event, this process has been well shown to promote tumor initiation and progression; however little is known how such epigenetic silencing can contribute to tumor metastasis. The PRKD1 gene encodes Protein Kinase D1 (PKD1), a serine/threonine kinase expressed in epithelial cells of the normal mammary gland that maintains the epithelial phenotype of normal breast cells and prevents epithelial-to-mesenchymal transition (EMT). PKD1 is also a critical suppressor of tumor cell invasion and is silenced in expression and activity during breast tumor progression. Here, we show that aberrant methylation of PRKD1 promoter region is not only correlated with the silencing of its expression but is also associated with invasiveness of breast cancer cell lines and with aggressiveness of breast tumors. Using the highly invasive MDA-MB-231 cells, we show that the inhibition of PRKD1 promoter methylation with the DNA methyltransferase inhibitor decitabine restores PKD1 expression and significantly decreases their invasive abilities in vitro. More importantly, in a tumor xenograft model it dramatically blocks tumor spread and metastasis to the lung in a PKD1-dependent fashion. Our data suggest that the status of epigenetic regulation of the PRKD1 promoter can provide valid information on the invasiveness of breast tumors, and therefore could serve as an early diagnostic marker. Moreover, targeted upregulation of PKD1 expression may be used as a therapeutic approach to reverse the invasive phenotype of breast cancer cells. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-24.