Basal-like breast cancer (BLBC) exhibits an aggressive clinical history, with development of recurrence, distant metastasis, shorter survival, and usually occurs in young women. BLBC intrinsically possesses many epithelial-mesenchymal transition (EMT) characteristics and cancer stem cell (CSC)-like features, suggesting that activation of EMT program generates high-grade invasive cells with CSC-like traits in BLBC. Our long-term goal is to discover the intrinsic factors within tumor cells and the extrinsic signals from tumor microenvironments that regulate EMT, and to identify molecules that may serve as druggable targets for treating this deadly disease. In the last several years, we have systematically studied the role of Snail and the molecular mechanism by which Snail represses E-cadherin expression in BLBC. Our study clearly indicates that Snail is one of the key intrinsic factors within tumor cells responsible for EMT;our study also implies that the inflammatory tumor microenvironment provides an extrinsic signal for EMT. However, how the extrinsic tumor milieu of BLBC is initiated and built up, despite its paramount importance, remains unaddressed. Recently, we found that expression of the X-box binding protein (XBP1) was significantly reduced in BLBC from human breast tumor samples and mouse breast cancer tissues. Snail suppressed XBP1 expression and resulted in a significant upregulation of CCL2, a major chemokine for tumor associated macrophages (TAMs) and lymphocytes. XBP1 is a key molecule in the most conserved "unfolded-protein response" (UPR) signaling pathway that cells use to cope with environmental and cellular stresses in endoplasmic reticulum (ER). Loss of XBP1 results in "unresolved ER stress", which signals endogenous cellular injury, triggering leukocyte infiltration, and a significant boost of inflammatory responses in target tissues. We hypothesize that the loss of XBP1 by Snail-mediated repression ignites an "inside out" signal for recruiting TAMs and lymphocytes, which establish an inflammatory/wound stroma to further boost EMT and cultivate CSC-like traits in BLBC by providing additional cytokines and growth factors. The objective of this proposal is to characterize the repression of XBP1 by Snail and explore therapeutic interventions that will disrupt this vicious cycle and thereby restore ER homeostasis using a newly developed specific Snail inhibitor. Guided by strong preliminary data, we will test this hypothesis by pursuing three specific aims: (1) to determine the molecular mechanisms responsible for Snail-mediated XBP1 repression in BLBC;(2) to delineate why loss of XBP1 enhances inflammation in BLBC;and (3) to elucidate the functional roles of XBP1 in vivo. Our proposal is innovative and significant, because it will not only open a new paradigm that significantly affects our views on the co- evolvement of tumor cells and their microenvironments in breast cancer progression and metastasis but will also lay groundwork for developing new therapeutic strategies against this disease.

Public Health Relevance

Our proposal is innovative since we will have a significant impact to public health through its potential to influence cancer treatment. The knowledge gained will expand our understanding of the co-evolvement between tumor cells and their microenvironments in tumor progression and metastasis. When successfully completed, these studies will provide insights for the development of novel interventions to prevent and treat metastatic basal-like breast cancer.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA125454-07
Application #
8698337
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Lexington
State
KY
Country
United States
Zip Code
40506
Lin, Yiwei; Dong, Chenfang; Zhou, Binhua P (2014) Epigenetic Regulation of EMT: The Snail Story. Curr Pharm Des 20:1698-705
Lin, Yiwei; Kang, Tiebang; Zhou, Binhua P (2014) Doxorubicin enhances Snail/LSD1-mediated PTEN suppression in a PARP1-dependent manner. Cell Cycle 13:1708-16
Shi, Jian; Wang, Yifan; Zeng, Lei et al. (2014) Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer. Cancer Cell 25:210-25
Dong, C; Wu, Y; Wang, Y et al. (2013) Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer. Oncogene 32:1351-62
Dong, Chenfang; Yuan, Tingting; Wu, Yadi et al. (2013) Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell 23:316-31
Wu, Yadi; Wang, Yifan; Yang, Xiuwei H et al. (2013) The deubiquitinase USP28 stabilizes LSD1 and confers stem-cell-like traits to breast cancer cells. Cell Rep 5:224-36
Dong, Chenfang; Wu, Yadi; Yao, Jun et al. (2012) G9a interacts with Snail and is critical for Snail-mediated E-cadherin repression in human breast cancer. J Clin Invest 122:1469-86
Li, Junlin; Zhou, Binhua P (2011) Activation of ýý-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters. BMC Cancer 11:49
Wang, Yifan; Zhou, Binhua P (2011) Epithelial-mesenchymal transition in breast cancer progression and metastasis. Chin J Cancer 30:603-11
Lin, Yiwei; Wu, Yadi; Li, Junlin et al. (2010) The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-specific demethylase 1. EMBO J 29:1803-16

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