Breast cancer remains one of the leading causes of death in women and most patients die from the tumor metastasis. Our long-term goal is to understand the molecular mechanisms of metastasis so that novel therapeutic strategy can be designed. EMT (epithelial to mesenchymal transition) is a determining step for a cancer cell to progress from a non-invasive to invasive state. Disruption of intercellular adhesion via loss of E- cadherin, the defining event for EMT, is often correlated with gain of the matrix metalloproteinases (MMP) that catalyze proteolytic matrix remodeling important for tumor cell invasion. Such a correlation has been found in invasive breast cancer. However how EMT is regulated during and contributes to breast cancer metastasis is largely unknown. We previously identified Kr?ppel-like transcription factor 8 (KLF8) as a downstream effector of FAK that plays a crucial role in breast cancer metastasis. Recently, we found that KLF8 is important for oncogenic transformation and overexpressed in invasive human breast cancer, suggesting an uninvestigated role for KLF8 in breast cancer metastasis. Our preliminary studies, using inducible and constitutive expression of KLF8 in MCF-10A cells, suggest that KLF8 is a potent inducer of EMT and invasion by repressing E- cadherin and activating MMP9, MMP2 and MT1-MMP. We also show that KLF8 plays a key role in the loss of E-cadherin and gain of the MMPs in invasive human breast cancer cells and that aberrant KLF8 elevation is tightly correlated with the loss of E-cadherin in patient specimens. Finally, our pilot studies suggest a role for KLF8 in supporting MDA-MB-231 lung metastasis. These results strongly support our hypothesis that KLF8 promotes breast cancer metastasis by initiating EMT and invasion through repression of E-cadherin and activation of the MMPs. We propose three specific aims to test this hypothesis using in semi-in vivo 3D acinus culture and in vivo mouse models and our MCF-10A cells expressing inducible KLF8 and MDA-MB-231 cells expressing inducible KLF8 sh RNA.
In Aim 1, we will determine the role of E-cadherin and the MMPs in KLF8- induced EMT and invasion by genetically modifying these proteins.
In Aim 2, we will identify the molecular mechanisms by which E-cadherin, the MMPs and intergrin-FAK signaling interplay to regulate KLF8-induced EMT and invasion using genetic, biochemical or pharmacological approaches.
In Aim 3, we will determine the role of KLF8 in tumor metastasis using a mouse model of human breast cancer and bioluminescence imaging. We will also evaluate role for other EMT regulators such as Snails, ZEBs and Twist in the regulation of metastasis by KLF8. Completion of this project will shed new lights on mechanisms responsible for breast cancer metastasis which may leads to new therapeutic intervention.

Public Health Relevance

Our identification of KLF8 as an inducer of EMT and invasion and a regulator of E-cadherin and MMPs is novel and significant. Results derived from this proposal will shed new lights on mechanisms responsible for breast cancer metastasis which may leads to new therapeutic intervention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Woodhouse, Elizabeth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Central Florida
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Mukherjee, Debarati; Lu, Heng; Yu, Lin et al. (2016) Krüppel-like factor 8 activates the transcription of C-X-C cytokine receptor type 4 to promote breast cancer cell invasion, transendothelial migration and metastasis. Oncotarget 7:23552-68
Zhao, Jihe (2016) Cancer stem cells and chemoresistance: The smartest survives the raid. Pharmacol Ther 160:145-58
Li, Tianshu; Lu, Heng; Mukherjee, Debarati et al. (2015) Identification of epidermal growth factor receptor and its inhibitory microRNA141 as novel targets of Krüppel-like factor 8 in breast cancer. Oncotarget 6:21428-42
Xiang, Xuan; Mei, Hong; Zhao, Xiang et al. (2015) miRNA-337-3p suppresses neuroblastoma progression by repressing the transcription of matrix metalloproteinase 14. Oncotarget 6:22452-66
Zhao, Jihe (2014) KLF8: so different in ovarian and breast cancer. Oncoscience 1:248-249
Lu, H; Hu, L; Yu, L et al. (2014) KLF8 and FAK cooperatively enrich the active MMP14 on the cell surface required for the metastatic progression of breast cancer. Oncogene 33:2909-17
Lu, H; Wang, X; Urvalek, A M et al. (2014) Transformation of human ovarian surface epithelial cells by Krüppel-like factor 8. Oncogene 33:10-8
Prosdocimo, Domenick A; Anand, Priti; Liao, Xudong et al. (2014) Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism. J Biol Chem 289:5914-24
Li, T; Lu, H; Shen, C et al. (2014) Identification of epithelial stromal interaction 1 as a novel effector downstream of Krüppel-like factor 8 in breast cancer invasion and metastasis. Oncogene 33:4746-55
Malhotra, Astha; Zhang, Xiaolei; Turkson, James et al. (2013) Buffer-stable chitosan-polyglutamic acid hybrid nanoparticles for biomedical applications. Macromol Biosci 13:603-13

Showing the most recent 10 out of 24 publications