Cancer stem cells (CSCs) play a critical role in breast cancer progression and chemoresistance. Recently, we found that induction of an epithelial-mesenchymal transition (EMT) in breast cancer cells confers stem cell attributes. We also identified the Forkhead transcription factor FOXC2 as an orchestrator of the mesenchymal program underlying EMT and a key regulator of metastatic competence. Our preliminary studies show that suppression of FOXC2 leads to reversion of EMT and loss of functional stem cell properties. Moreover, FOXC2 expression is higher in stem cells isolated from normal mammary tissues or mammary epithelial cell lines. This apparent positioning of FOXC2 at the crossroads of EMT and breast cancer stem cells suggests that it or its effectors are essential for the sustainment and/or functioning of breast cancer cells with mesenchymal and stem cell properties. In this proposal, we will employ a dual systems approach - an in vitro cell culture model and a Foxc2 conditional knockout mouse - to delineate the pleiotropic functions of Foxc2 in normal breast homeostasis and cancer progression. We will cross Foxc2 conditional knockouts to metastasis-prone transgenics to determine the consequences of Foxc2 ablation on tumor initiation and metastasis and test the hypothesis that Foxc2 is a critical regulator of stem-like attributes and resistance to chemotherapy in vivo. In addition, we have identified PDGFR-B as a putative druggable target downstream to FOXC2 and we will evaluate the efficacy of PDGFR-targeted agents in eradicating FOXC2-expressing EMT-derived CSCs. Thus this project will improve our understanding of the role of CSCs and EMT in breast cancer progression and will suggest putative FOXC2 molecular effectors that may be exploited to target metastatically-competent cells with EMT/CSC attributes.

Public Health Relevance

Metastasis and resistance to chemotherapy are the major causes of breast cancer-related mortality. Cancer stem cells (CSCs) play critical roles in both these processes, and we recently found that CSCs can be generated by an epithelial-mesenchymal transition (EMT), a latent embryonic process that has been shown to promote breast cancer progression. By using in vitro and in vivo models, we will characterize the pleiotropic functions of FOXC2 as a central mediator of EMT, stemness, metastatic competence and drug resistance, and the expected results will suggest possible molecular targets that may be exploited to selectively treat metastatic and resistant breast cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA155243-04
Application #
8616354
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2011-03-16
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
4
Fiscal Year
2014
Total Cost
$294,716
Indirect Cost
$104,630
Name
University of Texas MD Anderson Cancer Center
Department
Pathology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Yam, Clinton; Mani, Sendurai A; Moulder, Stacy L (2017) Targeting the Molecular Subtypes of Triple Negative Breast Cancer: Understanding the Diversity to Progress the Field. Oncologist 22:1086-1093
Rigoutsos, Isidore; Lee, Sang Kil; Nam, Su Youn et al. (2017) N-BLR, a primate-specific non-coding transcript leads to colorectal cancer invasion and migration. Genome Biol 18:98
Pietilä, Mika; Vijay, Geraldine V; Soundararajan, Rama et al. (2016) FOXC2 regulates the G2/M transition of stem cell-rich breast cancer cells and sensitizes them to PLK1 inhibition. Sci Rep 6:23070
Zhao, Weina; Prijic, Sara; Urban, Bettina C et al. (2016) Candidate Antimetastasis Drugs Suppress the Metastatic Capacity of Breast Cancer Cells by Reducing Membrane Fluidity. Cancer Res 76:2037-49
Paranjape, A N; Soundararajan, R; Werden, S J et al. (2016) Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties. Oncogene 35:5963-5976
Werden, S J; Sphyris, N; Sarkar, T R et al. (2016) Phosphorylation of serine 367 of FOXC2 by p38 regulates ZEB1 and breast cancer metastasis, without impacting primary tumor growth. Oncogene 35:5977-5988
Jolly, Mohit Kumar; Tripathi, Satyendra C; Jia, Dongya et al. (2016) Stability of the hybrid epithelial/mesenchymal phenotype. Oncotarget 7:27067-84
Dhawan, Andrew; Madani Tonekaboni, Seyed Ali; Taube, Joseph H et al. (2016) Mathematical modelling of phenotypic plasticity and conversion to a stem-cell state under hypoxia. Sci Rep 6:18074
Pietilä, M; Ivaska, J; Mani, S A (2016) Whom to blame for metastasis, the epithelial-mesenchymal transition or the tumor microenvironment? Cancer Lett 380:359-68
Boareto, Marcelo; Jolly, Mohit Kumar; Goldman, Aaron et al. (2016) Notch-Jagged signalling can give rise to clusters of cells exhibiting a hybrid epithelial/mesenchymal phenotype. J R Soc Interface 13:

Showing the most recent 10 out of 22 publications