Over the past twenty years, studies have shown that epithelial cancers grow in a specific environment characterized by tumor-induced changes ofthe infiltrating immune cells. This symbiotic relationship is critical for tumor growth and more importantly for tumor metastasis. Clearly a better understanding of these processes and the tumor types associated with each is critical to enhancing our understanding and treatment of malignant disease. During that same time period, it has been clear that the traditional approach to evaluate breast cancer using tumor histology does not adequately reflect the diversity of biology and the heterogeneity of this disease. As a result, new approaches to classifying breast cancer have been generated. The most commonly used, pioneered by this SPORE program, utilizes the expression of an intrinsic set of genes generated using cDNA microarray technology. Four different intrinsic subtypes were described-luminal A, HER-2-enriched, basal-like and normal-breast like. Interestingly, these different subtypes were associated with different clinical outcomes. Most recently, the Perou laboratory has identified a fifth subtype that is enriched in genes associated with tumor initiating cells and epithelial to mesenchymal transition. Patients with this subtype termed """"""""claudin-low"""""""" have the poorest survival compared to patients with the other intnnsic subtypes. Our group has found that the claudin-low subtype, medullary cancer and some basal-like tumors are heavily infiltrated with immune cells. Quite recently we have found that the immune Infiltrate is critical to the growth and metastasis of these tumors. The immune infiltration by T and B cells, macrophages, NK cells and myeloid-derived suppressor cells is due to the generation by these tumors and the surrounding stroma of proteins important in migration and invasion. The current project will focus on enhancing our understanding of how these immune cells potentiate local and metastatic tumor grov^h of claudin-low, medullary cancer and basal-like tumors. Additionally, we will use therapies that specifically target these immune cells in combination with conventional therapies as a novel approach to the treatment of these tumors.

Public Health Relevance

Breast cancer is the most common malignancy in women in the United States and the second leading cause of malignant death. We have found that a new subtype, claudin-low, are heavily infiltrated with immune cells, which are critical to the growth of these tumors. The current project seeks to understand how these immune cells regulate tumor growth and to target immune and tumor cells as a novel approach to therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA058223-21
Application #
8723745
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
21
Fiscal Year
2014
Total Cost
$182,145
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Kohler, Racquel E; Gopal, Satish; Miller, Anna R et al. (2017) A framework for improving early detection of breast cancer in sub-Saharan Africa: A qualitative study of help-seeking behaviors among Malawian women. Patient Educ Couns 100:167-173
Mobley, Robert J; Raghu, Deepthi; Duke, Lauren D et al. (2017) MAP3K4 Controls the Chromatin Modifier HDAC6 during Trophoblast Stem Cell Epithelial-to-Mesenchymal Transition. Cell Rep 18:2387-2400
Sharma, Priyanka; López-Tarruella, Sara; García-Saenz, Jose Angel et al. (2017) Efficacy of Neoadjuvant Carboplatin plus Docetaxel in Triple-Negative Breast Cancer: Combined Analysis of Two Cohorts. Clin Cancer Res 23:649-657
Valle, Carmina G; Deal, Allison M; Tate, Deborah F (2017) Preventing weight gain in African American breast cancer survivors using smart scales and activity trackers: a randomized controlled pilot study. J Cancer Surviv 11:133-148
Hoffman, Joshua D; Graff, Rebecca E; Emami, Nima C et al. (2017) Cis-eQTL-based trans-ethnic meta-analysis reveals novel genes associated with breast cancer risk. PLoS Genet 13:e1006690
Mullooly, Maeve; Yang, Hannah P; Falk, Roni T et al. (2017) Relationship between crown-like structures and sex-steroid hormones in breast adipose tissue and serum among postmenopausal breast cancer patients. Breast Cancer Res 19:8
Zawistowski, Jon S; Bevill, Samantha M; Goulet, Daniel R et al. (2017) Enhancer Remodeling during Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacologic Targeting of the P-TEFb Complex. Cancer Discov 7:302-321
Visvanathan, Kala; Fackler, MaryJo S; Zhang, Zhe et al. (2017) Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study. J Clin Oncol 35:751-758
Heng, Yujing J; Lester, Susan C; Tse, Gary Mk et al. (2017) The molecular basis of breast cancer pathological phenotypes. J Pathol 241:375-391
Bowerman, Charles J; Byrne, James D; Chu, Kevin S et al. (2017) Docetaxel-Loaded PLGA Nanoparticles Improve Efficacy in Taxane-Resistant Triple-Negative Breast Cancer. Nano Lett 17:242-248

Showing the most recent 10 out of 548 publications