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)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA125454-08
Application #
8836396
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Jhappan, Chamelli
Project Start
2006-12-01
Project End
2018-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
8
Fiscal Year
2015
Total Cost
$277,369
Indirect Cost
$93,071
Name
University of Kentucky
Department
Biochemistry
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Yu, Qian; Zhou, Binhua P; Wu, Yadi (2017) The regulation of snail: on the ubiquitin edge. Cancer Cell Microenviron 4:
Lin, Yiwei; Wang, Yu; Shi, Qing et al. (2017) Stabilization of the transcription factors slug and twist by the deubiquitinase dub3 is a key requirement for tumor metastasis. Oncotarget 8:75127-75140
Wu, Yadi; Wang, Yu; Lin, Yiwei et al. (2017) Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradation. Nat Commun 8:14228
Zhou, Yuting; Rucker 3rd, Edmund B; Zhou, Binhua P (2016) Autophagy regulation in the development and treatment of breast cancer. Acta Biochim Biophys Sin (Shanghai) 48:60-74
Wang, Yifan; Liu, Jingyi; Ying, Xuhua et al. (2016) Twist-mediated Epithelial-mesenchymal Transition Promotes Breast Tumor Cell Invasion via Inhibition of Hippo Pathway. Sci Rep 6:24606
Liu, Shuli; Ye, Dongxia; Xu, Dongliang et al. (2016) Autocrine epiregulin activates EGFR pathway for lung metastasis via EMT in salivary adenoid cystic carcinoma. Oncotarget 7:25251-63
Liu, Jingyi; Lin, Pengnian Charles; Zhou, Binhua P (2015) Inflammation fuels tumor progress and metastasis. Curr Pharm Des 21:3032-40
Shi, Jian; Cao, Jingying; Zhou, Binhua P (2015) Twist-BRD4 complex: potential drug target for basal-like breast cancer. Curr Pharm Des 21:1256-61
Yin, Yuanqin; Deng, Xinyu; Liu, Zeyi et al. (2014) CD151 represses mammary gland development by maintaining the niches of progenitor cells. Cell Cycle 13:2707-22
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

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