In spite of therapeutic advances, up to 25% of luminal breast cancers will eventually develop resistance to endocrine therapy and develop metastatic disease. The underlying mechanism causing ER-positive, steroid responsive tumours to develop a resistant, metastatic phenotype remains unresolved. Previous work from our group and others has identified the P160 protein SRC-1 as a significant predictor of recurrence on endocrine therapy. The purpose of this study is to further examine downstream SRC-1 targets in the context of endocrine resistant breast cancer.
We adopted a global approach to define the transcriptional targets of SRC-1. SRC-1 ChIP sequencing in endocrine resistant luminal B breast cancer cells was combined with SRC-1 gene expression array analysis. This identified a number of pathways significantly elevated following tamoxifen treatment, including a number involved in cellular adhesion. From these pathways, A Disintegrin And Metalloproteinase-22 (ADAM22) was selected for further study.
Knockout studies confirmed ADAM22 as a tamoxifen dependent SRC-1 target gene. Functional assays including migration, three dimensional cell culture and adhesion independence growth assays confirmed a role for ADAM22 in promoting a migratory, aggressive phenotype. Samples from two separate TMAs comprising over 1,000 patients confirmed that ADAM22 is associated with poor disease free survival in breast cancer patients.
LGI1 is a naturally occurring neuropeptide which acts on an inhibitory manner on ADAM22 in the central nervous system. Using molecular modelling, a novel peptide mimetic targeting the disintegrin binding domain of ADAM22 was designed. Treatment with this peptide mimetic restored endocrine resistant cells to a less aggressive, sensitive phenotype, similar to the effect seen with knockdown of ADAM22. Moreover in an endocrine resistant xenograft model, treatment with the LGI1 mimetic significantly reduced primary and metastatic tumour burden in tamoxifen treated animals.
We have used next-generation sequencing techniques to identify a novel therapeutic target in endocrine resistant, metastatic breast cancer. Rational drug design has been used to manufacture a therapeutic peptide against ADAM22. A combination of in vitro, in vivo and patient studies has confirmed a role for ADAM22 in metastatic breast cancer. Our novel peptide mimetic may form a future basis for targeting ADAM22 in endocrine resistant disease.
Citation Format: Jarlath C Bolger, Damian McCartan, Damir Vareslija, Ailis Fagan, Christopher Byrne, Marie McIlroy, Peadar O'Gaora, Arnold D Hill, Leonie S Young. Global characterisation of the SRC-1 transcriptome and rational drug design results in the identification of a novel peptide targeting ADAM22 in endocrine resistance [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-02.