Identifying Oncogenic Drivers of Poor Outcome in Triple Negative Breast Cancer

Abstract

Triple Negative Breast cancers (TNBC) are defined by an absence of HER2 amplification, and a lack of estrogen (ER) and progesterone (PR) expression. They are an especially aggressive and poor prognosis subtype of Breast cancer and are associated with high incidence of chemoresistance and metastasis. There are currently no biomarkers to predict a patient’s prognosis and whether they will respond to treatment or develop metastasis, nor is there an effective targeted therapy for these patients. Thus, there is a dire unmet clinical need to identify oncogenic drivers which could be used to stratify patients or as potential targeted stratified therapies. In normal Breast cells TGFβ2-pSMAD2/3 signalling functions as a tumour suppressor to prevent uncontrolled proliferation, however in TNBC tumours it drives EMT and metastasis. However, the mechanism for this drastic switch in function has remained unanswered. In this study we identified that TGFβ2, YWHAZ and GLI2 are upregulated in poor outcome TNBC cell lines work together with FOXC1 to subvert the growth control effects of TGFβ2-pSMAD2/3 signalling towards transcriptional activation of EMT and metastasis driving genes. Furthermore, we identified this dysregulation occurs at the protein level with GLI2 requiring to interact with YWHAZ to partner with pSMAD2/3, to translocate to the nucleus where it act as a transcriptional coactivator and performs it transcriptional activation of genes which are also upregulated in poor outcome TNBC tumours and are capable of upregulating metastasis. Furthermore, we identified that this TGFβ2-YWHAZ-GLI2-FOXC1 axis is targetable through a GLI2 inhibitor GANT61 which although did not synergise with FEM treatment, did negatively regulate the metastatic phenotype of TNBC cells. Knockdown of TGFβ2 was sufficient to reduce tumour growth and onset invivo, which holds great promise for downstream targeted treatment of the TGFβ2 pathway via GLI2 inhibitors in the invivo setting. This study holds potential to answer a dire unmet clinical need and identifies that TGFβ2, YWHAZ, GLI2 and FOXC1 hold promise for the development of biomarkers and targeted therapies for these poor prognosis patients.

Date of Award	Jul 2020
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	Paul Mullan (Supervisor) & Niamh Buckley (Supervisor)