Abstract P2-01-08: The potential role of CTNND1 (catenin (cadherin-associated protein), Delta 1) in breast cancer bone metastasis

Background: The bone is a frequently visited site by breast cancer cells. Most women who die of metastatic breast cancer would already have bone metastases, whether they are micro- or macro-metastases. Metastatic bone metastasis from breast cancer is mostly osteolytic, with reasons unclear and little in vitro and in vivo studies exploring the osteolytic nature of bone metastasis. In the present study, we investigated the potential role of CTNND1, Catenin (Cadherin-Associated Protein) Delta 1, in the context of bone metastasis of breast cancer. Materials and Methods: In order to identify potential genes involved in bone metastasis, we established a novel in vitro model named Bone Matrix Extract (BME) which was extracted from human femur and used to mimic the bone environment. Full profile of gene expression in response to BME was conducted using Ampliseq technology. Potential genes associated with bone metastasis was examined in a clinical breast cohort containing both cancer and normal tissues (n = 103), collected immediately following surgery. Gene transcript levels were quantified using QPCR and analysed against patient9s pathological information and clinical outcome. We generated a series of cell models by knocking down and over-expressing one of the most relevant genes, CTNND1, using siRNA, sh-RNA, ribozyme transgenes and insertion of full coding sequence containing plasmids. Function assays including Matrigel based-adhesion, cancer cell-osteobalstic cell contact, proliferation, transwell invasion and migration were used to investigate the changes of biological features after interfering with CTNND1 expression in relation to BME / co-culture models. Results: CTNND1 was down regulated in all breast epithelial cells following BME treatment at both mRNA and protein level. From the clinical cohort, we found that compared with benign tissue, breast cancer tissues had significantly decreased CTNND1 transcript expression. Reduced CTNND1 was associated with advanced TNM stage and poor distant metastasis, local recurrence and bone metastasis. We went on to knockdown CTNND1 by siRNA, ribozyme as well as lenti-shCTNND1 transfection in MCF-10A and MDA-231 cells and overexpressed CTNND1 in MCF-7 cells. In vitro study demonstrated that knockdown of CTNND1 expression led to decreased capacity of Matrigel-adhesion, migration and invasion but increased cancer cell-osteobalstic cell adhesion. No effects were observed on cell proliferation after altering CTNND1 expression, in the presence or absence of BME. Conclusions: In this initial study on CTNND1 in breast cancer, our current data suggests that lower transcript expression of CTNND1 associates with a poorer patient prognosis. CTNND1 reduction may play a role in the progression of breast cancer bone metastasis. Citation Format: Gong C, Andrew A, Feng Y, Owen S, Liang G, Davies E, Song E, Jiang W. The potential role of CTNND1 (catenin (cadherin-associated protein), Delta 1) in breast cancer bone metastasis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-08.