Breast cancer, known as the most common malignancy in women, causes more than 500,000 death world widely each year. Since breast cancer is often refractory to therapy due to the late detection and the efficacy of existing therapeutics is limited, there is a great urgency to improve early diagnosis of breast cancer, and also to identify and validate new potential therapeutic targets.Ubiquitin is found in intracellular and extracellular fluids and is involved in regulation of numerous cellular processes. However, it is unclear that the balance between intracellular and extracellular ubiquitin machinery in patients, and how dynamics of ubiquitin regulatory system contribute to the action and cellular signaling pathways in breast cancer. We previously showed that SAG (sensitive to apoptosis gene)-dependent UPS (ubiquitin-proteasome system) plays a pivotal role at the crossroads between immune-overactivation and pro-tumorigenesis. Overexpressed SAG-dependent UPS in the carcinoma tissues favors and exacerbates the vicious cycle of tumorigenic microenvironment for the progression of hepatocellular carcinoma. In this project, our preliminary data shows that SAG and two F-boxes are significantly upregulated in human breast cancer tissues. However, the role of SAG-UPS and corresponding F-boxes involved in breast cancer development and metastasis is unclear. On the other hand, extracellular ubiquitin is reported involve in the immune-overactivation diseases which is beneficial to tumour microenvironment. It is proposed that cancer cells can develop strategies to escape nature killer (NK) cell attack via manipulating tumour microenvironment. Being the primary responders during infection challenges, NK and macrophage cells play crucial roles in cancer immunosurveillance. However, the role of extracellular/free ubiquitin in the collaborative role of NKs and macrophages in cancer immunosurveillance is still unclear. Taken together, we hypothesize that ubiquitin machinery may manipulate breast cancer carcinogenesis, metastasis and tumour microenvironment via both intracellular (SAG-UPS) and extracellular (free ubiquitin) strategies. Thus, in this project we aim to:(1) To investigate the role of intracellular ubiquitin via SAG-dependent UPS in breast cancer carcinogenesis and metastasis.(2) To delineate the collective roles between extracellular/free ubiquitin and intracellular UPS in breast cancer development and metastasis. (3) To clarify the effects by extracellular/free ubiquitin in the collaborative role of NKs and macrophages in tumor cells survival/death.By elucidating the ubiquitin regulatory machinery involved in breast cancer development, metastasis and tumor microenvironment, we will have profound impact in identifying new molecular targets and therapies for efficient tumour microenvironment early diagnosis, metastasis prediction, prevention and treatment.
|Effective start/end date||8/1/18 → 7/31/20|
- Intracellular/Extracellular ubiquitin machinery
- Breast cancer development and metastasis
- Tumour microenvironment
- SAG (sensitive to apoptosis gene)-dependent UPS (ubiquitin-proteasome system)
- Free ubiquitin-CXCR4 (CXC chemokine receptor 4) axis