Tamoxifen is a useful therapy for some but not all breast cancer patients with estrogen receptor positive (ER+) tumors. Second line hormonal therapies have limited effectiveness in patients who have failed following a response to tamoxifen treatment for metastatic disease or relapsed after receiving adjuvant tamoxifen therapy. A better understanding of the mechanisms responsible for acquired tamoxifen resistance should provide the conceptual basis for additions or modifications to current treatment regimens that will extend or restore sensitivity or prolong the therapeutic effect of tamoxifen and other selective estrogen receptor response modifiers (SERMS). Recent clinical data suggests that the extent of neoangiogenesis ongoing within a patient's tumor is inversely related to the extent derived from adjuvant hormonal therapy. Our own preliminary and published data indicate that paracrine effects of angiogenic growth factor production by ER+ human breast tumor cells growing as xenografts in athymic nude mice can reduce the effectiveness of tamoxifen as a cytostatic or cytotoxic agent. The studies proposed in this project are designed to use these cell lines as model system to identify the molecular mechanisms responsible for this effect.
In aims 1 and 2, ER+ breast tumor cells engineered to over-express the165 amino acid form of VEGF-A in a tetracycline regulated manner will be used to determine how angiogenic growth factor product alters the balance of cell proliferation and cell death within xenografts excised from tamoxifen treated mice.
In aim 3 we will determine whether angiogenic growth factor over-expression.
In aim 4, we will test the ability of novel VEGFR antagonists that are now in early phase clinical trials to restore tamoxifen sensitivity or prevent the development of new tumors when used in combination with tamoxifen in a NMU carcinogen induced rat mammary carcinoma model will also be explored.
In aim 5, we will perform a pilot clinical trial to determine if addition of a VEGFR antagonist to the treatment regimen can restore tamoxifen sensitivity to patients with recurrent metastatic breast cancer who either initially responded to tamoxifen treatment or relapsed following adjuvant therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
1P50CA089019-01
Application #
6403789
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2000-09-30
Project End
2005-09-30
Budget Start
Budget End
Support Year
1
Fiscal Year
2000
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Wielgos, Monica E; Zhang, Zhuo; Rajbhandari, Rajani et al. (2018) Trastuzumab-Resistant HER2+ Breast Cancer Cells Retain Sensitivity to Poly (ADP-Ribose) Polymerase (PARP) Inhibition. Mol Cancer Ther 17:921-930
Wielgos, Monica E; Rajbhandari, Rajani; Cooper, Tiffiny S et al. (2017) Let-7 Status Is Crucial for PARP1 Expression in HER2-Overexpressing Breast Tumors. Mol Cancer Res 15:340-347
Forero, Andres; Li, Yufeng; Chen, Dongquan et al. (2016) Expression of the MHC Class II Pathway in Triple-Negative Breast Cancer Tumor Cells Is Associated with a Good Prognosis and Infiltrating Lymphocytes. Cancer Immunol Res 4:390-9
McNally, Lacey R; Mezera, Megan; Morgan, Desiree E et al. (2016) Current and Emerging Clinical Applications of Multispectral Optoacoustic Tomography (MSOT) in Oncology. Clin Cancer Res 22:3432-9
Atherton, Daniel S; Sexton, Katherine C; Otali, Dennis et al. (2016) Factors Affecting the Use of Human Tissues in Biomedical Research: Implications in the Design and Operation of a Biorepository. Methods Mol Biol 1381:1-38
Li, Rong; Zhang, Kui; Penedo, Thuy Linh et al. (2016) The RANK Pathway in Advanced Breast Cancer: Does Src Play a Role? Appl Immunohistochem Mol Morphol 24:42-50
Walters, Beth; Thompson, Sunnie R (2016) Cap-Independent Translational Control of Carcinogenesis. Front Oncol 6:128
Wu, Lizhi; Chaudhary, Sandeep C; Atigadda, Venkatram R et al. (2016) Retinoid X Receptor Agonists Upregulate Genes Responsible for the Biosynthesis of All-Trans-Retinoic Acid in Human Epidermis. PLoS One 11:e0153556
Otali, D; Fredenburgh, J; Oelschlager, D K et al. (2016) A standard tissue as a control for histochemical and immunohistochemical staining. Biotech Histochem 91:309-26
Grizzle, William E; Gunter, Elaine W; Sexton, Katherine C et al. (2015) Quality management of biorepositories. Biopreserv Biobank 13:183-94

Showing the most recent 10 out of 211 publications