NF-kappaB signaling can regulate a diverse set of processes including proliferation, apoptosis, angiogenesis and inflammation. During the progression from normal mammary development to hyperplasia, primary tumor formation and finally to metastasis a complex interplay of these processes occurs. The proposed project will define the role of NF-kappaB signaling as a master regulator of these processes, integrating multiple processes and thereby determining ultimate physiological outcome. As such, modulation of NF-kappaB signaling represents an important strategy for therapeutic intervention and considerable research effort is being expended to identify inhibitors of NF-kappaB functional at various stages of the signaling cascade. Signaling pathways that are active are likely to be different during particular stages of tumorigenesis eg. normal development, primary tumor growth and metastasis. It is therefore important to understand the complexities of the regulatory pathways to determine the most efficacious points to target therapy and to minimize undesirable side effects. We propose utilizing several existing murine models to examine the effect of modulation of NF-kappaB activity within mammary epithelium on the continuum of mammary tumorigenesis. Our strategy will address both activation and inhibition of the classical p50/p65/lkappaBalpha pathway and stimulation of the alternative RelB/p1007p52 pathway. We will clarify the effects of modulating NF-kappaB activity during development, primary tumor formation and metastasis on critical processes such as proliferation, apoptosis, angiogenesis and inflammation. It is hypothesized that modulation of NF-kappaB activity will have significant effects at all stages of tumor development and progression on pathogenic outcome. These studies will provide powerful data that will increase our knowledge of the roles of NF-kappaB in mammary tumorigenesis, thus supporting the design of informed therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA113734-04
Application #
7808791
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Snyderwine, Elizabeth G
Project Start
2007-07-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$291,650
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Barham, Whitney; Chen, Lianyi; Tikhomirov, Oleg et al. (2015) Aberrant activation of NF-?B signaling in mammary epithelium leads to abnormal growth and ductal carcinoma in situ. BMC Cancer 15:647
Wilson, Andrew J; Saskowski, Jeanette; Barham, Whitney et al. (2015) Thymoquinone enhances cisplatin-response through direct tumor effects in a syngeneic mouse model of ovarian cancer. J Ovarian Res 8:46
Wilson, Andrew J; Saskowski, Jeanette; Barham, Whitney et al. (2015) Microenvironmental effects limit efficacy of thymoquinone treatment in a mouse model of ovarian cancer. Mol Cancer 14:192
Jin, Renjie; Yi, Yajun; Yull, Fiona E et al. (2014) NF-?B gene signature predicts prostate cancer progression. Cancer Res 74:2763-72
Barham, Whitney; Frump, Andrea L; Sherrill, Taylor P et al. (2013) Targeting the Wnt pathway in synovial sarcoma models. Cancer Discov 3:1286-301
Barham, Whitney; Sherrill, Taylor; Connelly, Linda et al. (2012) Intraductal injection of LPS as a mouse model of mastitis: signaling visualized via an NF-ýýB reporter transgenic. J Vis Exp :e4030
Zaynagetdinov, R; Stathopoulos, G T; Sherrill, T P et al. (2012) Epithelial nuclear factor-?B signaling promotes lung carcinogenesis via recruitment of regulatory T lymphocytes. Oncogene 31:3164-76
Zaynagetdinov, Rinat; Sherrill, Taylor P; Polosukhin, Vasiliy V et al. (2011) A critical role for macrophages in promotion of urethane-induced lung carcinogenesis. J Immunol 187:5703-11
Connelly, Linda; Barham, Whitney; Onishko, Halina M et al. (2011) NF-kappaB activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model. Breast Cancer Res 13:R83
Connelly, L; Barham, W; Onishko, H M et al. (2011) Inhibition of NF-kappa B activity in mammary epithelium increases tumor latency and decreases tumor burden. Oncogene 30:1402-12

Showing the most recent 10 out of 12 publications