I am an Assistant Member at Fox Chase Cancer Center (Philadelphia, PA) and I am submitting a K01 application to study the new biology of estrogen and fulvestrant action in aromatase inhibitor resistant breast cancer cells. Project Summary: Aromatase inhibitors (Als) are currently accepted as the standard care for the treatment of estrogen receptor (ER)-positive breast cancer. These agents prevent estrogen synthesis in postmenopausal women. One of the consequences of long-term estrogen deprivation (i.e., aromatase inhibition), however, is the development of acquired drug resistance. To further study the development of acquired resistance to Als, I have developed a panel of long-term estrogen deprived (LTED) breast cancer cell lines that were adapted to grow under estrogen-depleted conditions. The phenotype of these LTED cells is that they grow robustly in the absence of estrogen (i.e., resistant to estrogen deprivation), however, in the presence of physiologic concentrations of 17 (-estradiol (E2), these Al-resistant cells undergo cell death. The mechanism by which estrogen switches from being a growth stimulus (cancer-causing agent) to a killing (apoptotic) agent is not known. The goal of my research project is to investigate the new biology of E2 action in long-term estrogen deprived breast cancer cells. The hypothesis is that long-term estrogen deprivation alters the milieu of a select subset of breast cancer cells which sensitizes them to estrogen-induced death. The following research techniques will be used;Western blot analysis to measure protein expression, Real-Time polymerase chain reaction (PCR) to measure changes in mRNA levels, confocal microscopy to study protein translocalization, small interfering RNA (siRNA) and transfection analyses to suppress gene expression, cell invasion and migration assay to measure invasiveness and metastatic potential of Al-resistant cells, and chromatin immunoprecipitation (ChIP) assay to measure ER interaction with coregulatory proteins at estrogen-responsive promoters. Relevance of Research Project: The American Cancer Society has estimated that in 2006, approximately 212,920 women in the United States will be diagnosed with breast cancer and 40,970 will die. Breast cancer thus represents a major health problem;hence, a strategy to understand and subvert the acquisition of resistance to current treatment modalities would be a valuable therapeutic advantage.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA120051-05
Application #
8133667
Study Section
Subcommittee G - Education (NCI)
Program Officer
Ojeifo, John O
Project Start
2007-08-27
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$131,229
Indirect Cost
Name
Fox Chase Cancer Center
Department
Type
DUNS #
073724262
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Lui, Asona J; Geanes, Eric S; Ogony, Joshua et al. (2017) IFITM1 suppression blocks proliferation and invasion of aromatase inhibitor-resistant breast cancer in vivo by JAK/STAT-mediated induction of p21. Cancer Lett 399:29-43
Lui, Asona; New, Jacob; Ogony, Joshua et al. (2016) Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells. BMC Cancer 16:487
Ogony, Joshua; Choi, Hye Joung; Lui, Asona et al. (2016) Interferon-induced transmembrane protein 1 (IFITM1) overexpression enhances the aggressive phenotype of SUM149 inflammatory breast cancer cells in a signal transducer and activator of transcription 2 (STAT2)-dependent manner. Breast Cancer Res 18:25
Hayes, Erin L; Lewis-Wambi, Joan S (2015) Mechanisms of endocrine resistance in breast cancer: an overview of the proposed roles of noncoding RNA. Breast Cancer Res 17:40
Choi, Hye Joung; Lui, Asona; Ogony, Joshua et al. (2015) Targeting interferon response genes sensitizes aromatase inhibitor resistant breast cancer cells to estrogen-induced cell death. Breast Cancer Res 17:6
Jan, Rifat; Huang, Min; Lewis-Wambi, Joan (2012) Loss of pigment epithelium-derived factor: a novel mechanism for the development of endocrine resistance in breast cancer. Breast Cancer Res 14:R146
Maximov, Philipp; Sengupta, Surojeet; Lewis-Wambi, Joan S et al. (2011) The Conformation of the Estrogen Receptor Directs Estrogen-Induced Apoptosis in Breast Cancer: A Hypothesis. Horm Mol Biol Clin Investig 5:27-34
Sanzari, J K; Wambi, C; Lewis-Wambi, J S et al. (2011) Antioxidant dietary supplementation in mice exposed to proton radiation attenuates expression of programmed cell death-associated genes. Radiat Res 175:650-6
Maximov, Philipp Y; Myers, Cynthia B; Curpan, Ramona F et al. (2010) Structure-function relationships of estrogenic triphenylethylenes related to endoxifen and 4-hydroxytamoxifen. J Med Chem 53:3273-83
Lewis-Wambi, Joan S; Jordan, V Craig (2009) Estrogen regulation of apoptosis: how can one hormone stimulate and inhibit? Breast Cancer Res 11:206

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