Metastatic relapse is the leading cause of death for patients with basal-like breast cancer (BLBC), the most aggressive subtype that accounts for ~15% of all breast cancers. BLBC tends to affect younger patients and metastasize to lung and brain. Systematic chemotherapy is the standard treatment for patients with BLBC tumors. Despite initial high response rates to chemotherapy, manifested by tumor regression, most patients (~85%) experience metastatic relapse within 10 years. Currently there is no effective way to treat or prevent metastatic relapse because we do not fully understand what enables tumor cells to escape cytotoxicity of chemotherapy. Our recent studies and analysis of The Cancer Genome Atlas (TCGA) data suggest that two distinct phenotypic states, MYC-driven proliferative and drug-sensitive state and HIF1A-driven invasive and drug-resistant state, coexist among BLBC tumor cells. We found that miR-18a-5p plays a key role in regulating phenotypic state of BLBC cells by suppressing HIF1A activation, and derepression of HIF1A due to miR-18a-5p downregulation is sufficient to convert tumor cells into a drug resistant state. We propose to examine whether increasing cellular content of miR-18a-5p to suppress HIF1A activation or inhibiting metabolic enzymes regulated by HIF1A can be used for therapeutic purpose to increase chemosensitivity of BLBC cells. The results from these studies will contribute to a broader understanding of the function of miRNAs in regulating cell phenotype, and advance our understanding of HIF1A-mediated drug resistance.

Public Health Relevance

Metastatic relapse is the leading cause of death for breast cancer patients. This proposed study is aimed to define the molecular events that promote tumor cell survival and metastasis and focuses on the application of miRNAs to improve efficacy of anticancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA197206-01A1
Application #
9092311
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2016-04-01
Project End
2018-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Pathology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38103
Fan, Meiyun; Pfeffer, Lawrence M (2018) The STAT3 and hypoxia pathways converge on Vasorin to promote stemness and glioblastoma tumorigenesis through Notch1 stabilization. Stem Cell Investig 5:35
Sethuraman, Aarti; Brown, Martin; Krutilina, Raya et al. (2018) BHLHE40 confers a pro-survival and pro-metastatic phenotype to breast cancer cells by modulating HBEGF secretion. Breast Cancer Res 20:117
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