Pro-invasive Effect of Proto-oncogene PBF Is Modulated by an Interaction with Cortactin

Abstract

Context:Metastatic disease is responsible for the majority of endocrine cancer deaths. New therapeutic targets are urgently needed to improve patient survival rates.Objective:The proto-oncogene PTTG1-binding factor (PBF/PTTG1IP) is overexpressed in multiple endocrine cancers and circumstantially associated with tumor aggressiveness. This study aimed to understand the role of PBF in tumor cell invasion and identify possible routes to inhibit its action.Design, Setting, Patients, and Interventions:Thyroid, breast, and colorectal cells were transfected with PBF and cultured for in vitro analysis. PBF and cortactin (CTTN) expression was determined in differentiated thyroid cancer and The Cancer Genome Atlas RNA-seq data.Primary Outcome Measure:Pro-invasive effects of PBF were evaluated by 2D Boyden chamber, 3D organotypic, and proximity ligation assays.Results:Our study identified that PBF and CTTN physically interact and co-localize, and that this occurs at the cell periphery, particularly at the leading edge of migrating cancer cells. Critically, PBF induces potent cellular invasion and migration in thyroid and breast cancer cells, which is entirely abrogated in the absence of CTTN. Importantly, we found that CTTN is over-expressed in differentiated thyroid cancer, particularly in patients with regional lymph node metastasis, which significantly correlates with elevated PBF expression. Mutation of PBF (Y174A) or pharmacological intervention modulates the PBF: CTTN interaction and attenuates the invasive properties of cancer cells.Conclusion:Our results demonstrate a unique role for PBF in regulating CTTN function to promote endocrine cell invasion and migration, as well as identify a new targetable interaction to block tumor cell movement.

MicroRNA-524-5p Functions as a Tumor Suppressor in a Human Pituitary Tumor-Derived Cell Line

“…For example, enhanced PBF levels potentially lead to cell invasion in breast cancer. In addition, PBF potentially elicits cell migration and invasion in thyroid cancer and hepatocellular carcinoma [24,25]. Moreover, PBF is associated with tumor recurrence, and its subcutaneous expression contributes to tumor formation in nude mice [22,25].…”

Functional consequences of the first reported mutations of the proto-oncogene PTTG1IP/PBF

“…2010 ). More recent investigations have demonstrated that PBF can induce invasion and migration in multiple cancer cells including thyroid and colorectal cells ( Watkins et al . 2016 ).…”

“…2016 ). Furthermore, these studies suggest that this occurs at least partly through interaction with cortactin (CTTN), a scaffold protein that acts predominantly at the cell periphery to promote actin polymerisation and can thus exert a potent influence upon cell movement and invasion ( Watkins et al . 2016 ).…”

Cortactin function in invadopodia

“…Overexpression of Cortactin is frequently observed in many types of cancers, including head and neck squamous cell carcinoma (HNSCC), 96 hepatocellular carcinoma, 97 breast cancer, 98 bladder cancer, 99 renal cell carcinoma, 100 esophageal squamous cell carcinoma, 101 colorectal adenocarcinoma, 102 melanoma, 103 osteosarcoma, 104 prostate cancer, 105 non-small cell lung cancer, 106 glioma, 107 epithelial ovarian cancer, 108 thyroid cancer 109 and B-cell chronic lymphocytic leukemia. 110 This overexpression is partially caused by the amplification of chromosome 11q13 where the CTTN gene is located.…”

“…A major conclusion from clinical studies is that Cortactin overexpression is associated with local invasion, lymph node metastasis and/or distal metastasis in almost every cancer in which it is overexpressed. 19,96,97,99,101,103,106,109,113 Moreover, several mouse models have provided evidence that Cortactin promotes the metastatic process. 97,101,121 Altogether, these findings indicate that Cortactin plays an important role in promoting tumor invasion and metastasis, consistent with the major role of Cortactin in regulating lamellipodia and invadopodia formation.…”