During development, certain genes are activated to stimulate cell proliferation, survival, migration, invasion, and neovascularization. These genes are often downregulated once organ development is complete. During carcinogenesis, the same genes are often re-activated, stimulating the same properties, but now out of context. Transcribed by one such gene, the homeobox protein and transcription factor Six1 is expressed during embryogenesis where it mediates the proliferation and survival of progenitor cells. It is lost in most differentiated tissues but re-expressed in a number of cancers including breast cancer. We have shown that when Six1 is expressed out of context in adult cells, it aberrantly promotes both proliferation and survival, contributing to tumorigenesis. Our preliminary evidence shows that Six1 also brings about an epithelial-to-mesenchymal-like transition (EMT) in cultured cells and promotes metastasis in vivo. Our proposed experiments are therefore directed at testing the following tri-partite hypothesis: Misexpression of Six1 after development is complete imparts not only a pro-proliferative and survival phenotype, but also a pro-migratory and invasive phenotype, contributing to metastatic disease. Acquisition of the invasive phenotype is due to a Six1-dependent increase in TGF- signaling. The resulting aggressive, metastatic mammary tumors remain dependent on Six1 for survival and for their aggressive behavior. In the proposed research we will provide definitive tests of these hypotheses both in vitro and in vivo and begin to decipher the molecular mechanism by which Six1 causes EMT and metastasis, focusing on the TGF- signaling pathway.
Our aims are: 1) To determine whether TR-I expression and signaling is required for Six1-mediated oncogenic EMT in cultured mammary epithelial cells;2) To determine in xenograft models whether Six1 overexpression is necessary and sufficient to cause metastatic breast disease, through upregulation of TGF- signaling;3) To use inducible transgenic models of Six1 overexpression to determine whether the invasive behavior of the resulting mammary tumors is due to TGF- signaling, and whether this behavior remains dependent on Six1. Relevance: Six1 is overexpressed in a much higher percentage of metastatic (90%) compared to primary breast cancers (50%) and its overexpression is often correlated with advanced tumor stage and worsened survival. Further, Six1 influences multiple stages of the tumorigenic process. For this reason therapeutic agents targeting Six1 have the potential to inhibit breast cancer at both early and later stages of disease progression. Because Six1 is lost in most adult tissues such therapeutic agents should have limited side effects. Project Narrative: Expression of the Six1 homeobox gene causes both tumor initiation and metastasis. Thus, therapeutic agents targeting Six1 have the potential to inhibit breast cancer at both early and later stages of disease progression. Further, because Six1 is expressed only during embryogenesis, and not in the adult, therapies that target Six1 should inhibit tumor cell growth and metastasis with limited side effects.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095277-09
Application #
7806644
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2002-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
9
Fiscal Year
2010
Total Cost
$252,180
Indirect Cost
Name
University of Colorado Denver
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Neelakantan, Deepika; Zhou, Hengbo; Oliphant, Michael U J et al. (2017) EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells. Nat Commun 8:15773
Zhou, Hengbo; Neelakantan, Deepika; Ford, Heide L (2017) Clonal cooperativity in heterogenous cancers. Semin Cell Dev Biol 64:79-89
Tavares, Andre L P; Cox, Timothy C; Maxson, Robert M et al. (2017) Negative regulation of endothelin signaling by SIX1 is required for proper maxillary development. Development 144:2021-2031
Towers, Christina G; Ford, Heide L (2016) A tale of two ends. Cell Cycle 15:1523-4
Neelakantan, Deepika; Drasin, David J; Ford, Heide L (2015) Intratumoral heterogeneity: Clonal cooperation in epithelial-to-mesenchymal transition and metastasis. Cell Adh Migr 9:265-76
Drasin, David J; Guarnieri, Anna L; Neelakantan, Deepika et al. (2015) TWIST1-Induced miR-424 Reversibly Drives Mesenchymal Programming while Inhibiting Tumor Initiation. Cancer Res 75:1908-21
Blevins, Melanie A; Towers, Christina G; Patrick, Aaron N et al. (2015) The SIX1-EYA transcriptional complex as a therapeutic target in cancer. Expert Opin Ther Targets 19:213-25
Towers, Christina G; Guarnieri, Anna L; Micalizzi, Doug S et al. (2015) The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p. Nat Commun 6:10077
Kohrt, Dawn; Crary, Jennifer; Zimmer, Marc et al. (2014) CDK6 binds and promotes the degradation of the EYA2 protein. Cell Cycle 13:62-71
Wang, Chu-An; Drasin, David; Pham, Catherine et al. (2014) Homeoprotein Six2 promotes breast cancer metastasis via transcriptional and epigenetic control of E-cadherin expression. Cancer Res 74:7357-70

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