- The role of DEPDC1 (DEP domain containing 1) in breast cancer aggressiveness
- Marotta, Carolina
Subject
- breast cancer
- mutantp53 DEPDC1 PIN1
- SCUOLA DI DOTTORATO DI RICERCA IN BIOMEDICINA MOLECOLARE
- BIO/11 BIOLOGIA MOLECOLARE
Description
- 2011/2012
- Metastasis formation is the final step in a solid tumour progression and is the most common cause of death in cancer patients. Therefore novel therapeutic strategies to prevent development of metastases have a potential impact on cancer mortality. In the last years, work from our lab has identified that, following oncogenic signalling, the phosphorylation-dependent prolyl-isomerase Pin1 amplifies mutant p53 oncogenic functions. In particular, we have demonstrated the relevance of a Pin1/mutant p53 axis in controlling directly a transcriptional “ten genes signature” program relevant for tumour growth and invasion. This signature includes genes relevant for breast cancer progression, correlated to poor outcome of breast cancer patients. Among these, we have unveiled DEPDC1 as a potent promoter of invasiveness and migration in MDA MB231 triple negative breast cancer (TNBC) cells. This gene is has been found overexpressed in different mouse and human tumours, such as breast carcinoma, colorectal and lung adenocarcinomas. The aim of my PhD work was to investigate the role of DEPDC1 in the cancer progression that is linked to cell-biological traits associated with high-grade malignancy - including motility, invasiveness and loss of polarity. We found that the high DEPDC1 expression level positively correlates with clinical outcome and aggressiveness in breast cancer and we demonstrate that DEPDC1 regulates important phenotypes involved in tumour formation and progression. First, we identified a role of DEPDC1 in promoting aggressive cancer phenotypes in vitro by regulating cell motility, polarity and proliferation. Second, we have evaluated that the establishment of lung metastasis in vivo in mice was reduced upon inhibition of DEPDC1. Third, we demonstrate the tumorigenic potential of DEPDC1-V1 alone or cooperating with oncogenic H-Ras on induction of malignant cell transformation. Finally, a preliminary data shows that DEPDC1 is also able to increase the efficiency of mammosphere formation of breast cancer cells, implicating a role in cancer stemness. Until now, our results support the strong impact of DEPDC1 on tumour progression while molecular pathways perturbed by DEPDC1 and by which drive the cancer progression are still unknown. However, our analysis of RNA-seq data upon silencing of DEPDC1, suggests the mechanism by which DEPDC1 could induce an aggressive phenotype altering the gene expression profile of breast cancer cells. Future studies will address the molecular networks by which DEPDC1 drives the metastatic cancer progression that could be useful for discovering the novel therapeutic targets and diagnostic markers in breast cancer.
- XXIV Ciclo
- 1983
Date
- 2013-05-08T08:12:38Z
- 2014-04-22T04:01:18Z
- 2013-04-22
Type
- Doctoral Thesis
Format
- application/pdf
Identifier
urn:nbn:it:units-10067