A critical aspect of tumor physiology is the sensation of oxygen in the microenvironment. Several studies have demonstrated that over-expression of the oxygen-responsive Hypoxia-Inducible Factor (HIF-1a ) protein in breast cancer correlates with poor prognosis, increased risk of metastasis and decreased survival. Moreover, hypoxic regions of tumors are a prominent source of tumor cells that are resistant to radiation and chemotherapy. It has also been proposed that hypoxia stimulates expansion of normal and cancer stem cells (CSCs). Yet, the specific contribution of HIF-1a to breast cancer progression and metastasis in relationship to CSCs remains undefined. Our long-term goal is to elucidate how hypoxia, through HIF-1a , regulates breast CSC/progenitor populations. The specific hypothesis that will be tested is that HIF-1a promotes CSC renewal, expansion and tumor-initiating ability through interactions with the Wnt/?-catenin signaling pathway, which potentiates the HIF-1a transcriptional response, resulting in increased primary tumor growth and metastatic potential. This will be tested in three specific aims. 1) To determine if HIF-1a promotes breast CSC renewal and tumor-initiating activity and if hypoxic exposure enhances CSC activity. Using novel HIF-1a wild type (WT) and null (KO) tumor cells derived from the MMTV-PyMT mouse model of breast cancer, we will address if hypoxia acts through HIF-1a to promote breast CSC renewal by comparing tumorsphere formation efficiencies and the frequency of tumor initiating cells in WT or KO cells that are sorted for cell surface markers that characterize murine mammary CSCs. 2) To determine if HIF-1a interacts with the Wnt/?-catenin signaling pathway to regulate breast CSC behavior. We will determine if ?-catenin activity is necessary for CSC activity in PyMT tumor cells, if HIF-1a and ?-catenin physically interact and if Wnt/?-catenin regulation of CSC activity is HIF-1a dependent by using TS and limiting dilution transplantation assays. 3) To investigate if HIF-1a -regulated CSC populations are enriched for metastasis and to investigate how HIF-1a promotes colonization and metastasis. Flow-sorted sub-populations of CSCs found to be regulated by HIF-1a in Aim 1 will be tested for enriched metastatic potential compared to parental cells using an intracardiac injection model of experimental metastases. Lentiviral transduction will be used to determine the contribution of HIF-1a regulated target genes to these processes. If our hypotheses that HIF-1a promotes breast tumor growth and metastasis through enhancing CSC activity via interactions with the Wnt/?-catenin are confirmed, then this could have significant impact on treatment paradigms, and would suggest that it may be possible to further refine treatments to specifically eradicate the breast CSC population through a combination of anti-HIF and anti- ?-catenin therapies. In addition, since the tumor-initiating niche may exist in a hypoxic microenvironment, it may also be possible to utilize anti-HIF therapies in combination with other adjuvant therapies to prevent metastatic spread or, in the future, for chemoprevention.

Public Health Relevance

Several lines of evidence suggest that the HIF-1a protein helps tumor cells to grow in the breast and to travel to distant sites in the body (metastasis), ultimately reducing patient survival. We now seek to address whether a key way by which HIF-1a promotes these processes is through regulation of behavior of a small fraction of cells within breast cancers that are believed to have enhanced self-renewal and tumor-initiating activity, the """"""""cancer stem cells"""""""". If HIF-1a regulates cancer stem cell function, then targeting the HIF-1a pathway for drug design would be beneficial to patients since interfering with a master regulator of the hypoxic response could disrupt multiple downstream processes essential to tumor growth and invasion, and may in fact, preferentially kill the cancer stem cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138488-03
Application #
8220935
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Watson, Joanna M
Project Start
2010-04-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$300,821
Indirect Cost
$96,425
Name
University of Tennessee Health Science Center
Department
Pathology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Regan Anderson, Tarah M; Ma, Shihong; Perez Kerkvliet, Carlos et al. (2018) Taxol Induces Brk-dependent Prosurvival Phenotypes in TNBC Cells through an AhR/GR/HIF-driven Signaling Axis. Mol Cancer Res 16:1761-1772
Lillo, M Angeles; Nichols, Cydney; Seagroves, Tiffany N et al. (2017) Bisphenol A Induces Sox2 in ER+ Breast Cancer Stem-Like Cells. Horm Cancer 8:90-99
Lillo, M Angeles; Nichols, Cydney; Perry, Chanel et al. (2017) Methylparaben stimulates tumor initiating cells in ER+ breast cancer models. J Appl Toxicol 37:417-425
Regan Anderson, Tarah M; Ma, Shi Hong; Raj, Ganesh V et al. (2016) Breast Tumor Kinase (Brk/PTK6) Is Induced by HIF, Glucocorticoid Receptor, and PELP1-Mediated Stress Signaling in Triple-Negative Breast Cancer. Cancer Res 76:1653-63
Sethuraman, Aarti; Brown, Martin; Seagroves, Tiffany N et al. (2016) SMARCE1 regulates metastatic potential of breast cancer cells through the HIF1A/PTK2 pathway. Breast Cancer Res 18:81
Brooks, Danielle L Peacock; Schwab, Luciana P; Krutilina, Raisa et al. (2016) ITGA6 is directly regulated by hypoxia-inducible factors and enriches for cancer stem cell activity and invasion in metastatic breast cancer models. Mol Cancer 15:26
Sodi, Valerie L; Khaku, Sakina; Krutilina, Raisa et al. (2015) mTOR/MYC Axis Regulates O-GlcNAc Transferase Expression and O-GlcNAcylation in Breast Cancer. Mol Cancer Res 13:923-33
Chen, Jianjun; Wang, Jin; Schwab, Luciana P et al. (2014) Benzimidazole analogs as potent hypoxia inducible factor inhibitors: synthesis, biological evaluation, and profiling drug-like properties. Anticancer Res 34:3891-904
Krutilina, Raisa; Sun, Wenlin; Sethuraman, Aarti et al. (2014) MicroRNA-18a inhibits hypoxia-inducible factor 1? activity and lung metastasis in basal breast cancers. Breast Cancer Res 16:R78
Slominski, A; Kim, T-K; Bro?yna, A A et al. (2014) The role of melanogenesis in regulation of melanoma behavior: melanogenesis leads to stimulation of HIF-1? expression and HIF-dependent attendant pathways. Arch Biochem Biophys 563:79-93

Showing the most recent 10 out of 17 publications