Novel mitotic regulators involved in breast cancer progression

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Novel mitotic regulators involved in breast cancer progression

 

Author: Lee, Lai Sheung
Title: Novel mitotic regulators involved in breast cancer progression
Degree: Ph.D.
Year: 2014
Subject: Breast -- Cancer -- Treatment.
Drug resistance in cancer cells
Paclitaxel
Hong Kong Polytechnic University -- Dissertations
Department: Dept. of Applied Biology and Chemical Technology
Pages: 319 leaves : ill. (some col.) ; 30 cm.
Language: English
InnoPac Record: http://library.polyu.edu.hk/record=b2696077
URI: http://theses.lib.polyu.edu.hk/handle/200/7412
Abstract: Taxanes are effective chemotherapeutic drugs for breast cancer treatment; however, the development of taxanes resistance remains a major obstacle in the clinic. FoxM1, Bmi-1 and Id1 are oncogenic transcription factors associated with breast cancer tumourigenesis and Taxol resistance, but the molecular mechanisms involved remain elusive. We propose to study a novel protein by which these factors may converge to confer Taxol resistance in breast cancers. Our data indicated that the proteasome subunit, PSMB3, was a common target of FoxM1, Bmi-1 and Id1. Consistently, we found higher level of PSMB3 in Taxol resistant breast cancer cells and in high grade clinical breast tumors. The significance of PSMB3 in breast cancer progression and Taxol resistance was evaluated using in vivo mouse model. We elucidated the detail mechanisms by which PSMB3 is activated by its three upstream regulators. In the first part of this study, our data supports the role of PSMB3 in conferring Taxol resistance and breast cancer development. We used live cell imaging techniques to visualize in real-time that targeting PSMB3 may be a viable strategy for overcoming Taxanes resistance in breast cancers. Recently, our team has uncovered the novel roles of FoxM1 and Id1 in mitotic exit regulation, which separate from their classical functions in transcriptional regulation. Due to their nature as being cytokinesis regulators, we hypothesize that dysregulation of PSMB3 in Taxol resistant breast cancers may likely be regulated by a mitotic component. This mitotic component should affect either spindle assembly checkpoint or cytokinesis function, which may in turn generate resistance to Taxol, the primary action of which is to arrest proliferating cells with active microtubule dynamics. Indeed, on our proteomics study, we revealed that PSMB3 is a downstream effector of the inner kinetochore component CENPH. CENPH overexpression can be detected in multiple epithelial cancers, including breast cancers. In the second part of this study, we validated by molecular studies that PSMB3 is regulated by CENPH. The events of how CENPH induced cytokinesis defects via PSMB3 were validated by molecular and live cell imaging studies. The significance of targeting PSMB3 in the bulk tumor mass was demonstrated in the first and second parts of this study. However, breast cancer is heterogeneous. One very rare population of cells in the tumour mass, CD44⁺/CD24⁺, is prevalent to favor distant metastasis and to confer extremely high Taxol resistance. In the final part of this study, the impact of targeting PSMB3 on breast cancer stem-like cells was investigated. PSMB3 appeared as a specific target in the CD44⁺/CD24⁺prevalent mammospheres in another set of proteomics data. We have confirmed the high expression level of PSMB3 in Taxol resistant CD44⁺/CD24⁺breast cancer stem-like cells; and that silencing PSMB3 resulted in loss of stemness in mammospheres. Given this important functional role of PSMB3 in maintaining breast cancer stem-like cells self-renewal, PSMB3 may directly impact taxanes resistance in breast cancer cells and breast cancer stem-like cells, and provide new insights into the design of novel therapeutic strategies for the prediction of taxanes sensitivity.

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