Abstract B29: Dissecting the effects of Brd4 short isoform on breast cancer progression

Breast cancer is one of the most common female malignancies in the United States with metastatic disease being the main contributor to breast cancer morbidity and mortality. Our lab previously identified BRD4, a member of the bromodomain family, as a regulator of breast cancer progression. Brd4 is a chromatin-modifying factor that regulates the expression of a large set of genes. Brd4 is normally expressed as two isoforms. The long isoform (Brd4-LF) contains two bromodomains in the N-terminus, an ET domain, a serine-rich SEED domain, and a proline-rich C-terminus. The short isoform (Brd4-SF) differs from the long isoform by a deletion of the proline-rich C-terminus and a three amino acid difference on the N-terminal domain. Previous studies in our laboratory indicate that these two isoforms have opposing effects on breast cancer progression. Highly metastatic mouse mammary tumor cells overexpressing Brd4-LF suppressed tumor growth and dissemination, whereas overexpression of Brd4-SF increased metastatic outgrowth in lungs. We have shown that these two isoforms are found in different compartments within the cell nucleus, leading to altered interaction with nuclear proteins. Brd4-LF is localized in the nuclear matrix while Brd4-SF is found in the nuclear envelope where it interacted with the LINC complex and known metastasis susceptibility proteins RRP1B and SIPA1. Given that these two isoforms reside in different subnuclear locations, we hypothesize that the isoforms bind to different sets of genes. To test this hypothesis we are utilizing the chromatin-immunoprecipitation sequencing (ChIP-seq) assay to characterize the genetic interactions associated with Brd4-SF. Identification of the Brd4-SF interacting genes will provide us with mechanistic insight into the underlying causes of the different metastatic outcomes promoted by the two isoforms, highlighting potential targets for future targeted therapies. Citation Format: Xinyi Zhu, Kent W. Hunter. Dissecting the effects of Brd4 short isoform on breast cancer progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B29.