University of Louisville
Nucleolin Acts as a Coactivator for COUP-TFII Regulation of Retinoic Acid Receptor b Transcription in T47D Human Breast Cancer Cells
Institution
University of Louisville
Faculty Advisor/ Mentor
Carolyn Klinge; Celia Emberts
Abstract
Tamoxifen (TAM) is an antiestrogen widely used in the treatment of patients whose breast tumors express estrogen receptor alpha (ERα) Of the patients initially responsive to the therapy, 40% eventually become resistant antiestrogens. The mechanisms involved in TAM resistance (TAM-R) have yet to be fully ascertained. The orphan nuclear receptor Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) is down-regulated in TAMR breast cancer cell lines. When COUP-TFII expression is restored in TAM-R cells, cell proliferation is again TAM inhibited. The mechanism for COUP-TFII’s restoration of TAMsensitivity is unknown. Recently, COUP-TFII and nucleolin were shown to oimmunoprecipitate and colocalize in breast cancer cells and human breast tumors; nevertheless, the implications of this interaction are unknown. Nucleolin is primarily in nucleoli; however, it is in the cytoplasm and plasma membrane of cancer cells. Nucleolin acts in chromatin remodeling, rDNA transcription, rRNA maturation, ribosome assembly, and nucleo-cytoplasmic transport. The anticancer drug AS1411, a G-quartet aptamer, targets nucleolin. Thus, the focus of my research was to determine if AS1411 inhibited COUP-TFII-regulated endogenous gene transcription in breast cancer cells. COUP-TFII increased transcription of the tumor suppressor retinoic acid receptor β gene (RARβ) in breast cancer cells. I found that AS1411 inhibited COUP-TFII stimulated RARβ transcription in T47D ERα+ human breast cancer cells. These data indicate that nucleolin acts as a coactivator for COUP-TFII-regulation of RARβ gene transcription and offers a possible mechanism for COUP-TFII’s restoration of TAM-sensitivity, i.e., by increasing differentiation as indicated by an increase in RARβ tumor suppressor expression.
Nucleolin Acts as a Coactivator for COUP-TFII Regulation of Retinoic Acid Receptor b Transcription in T47D Human Breast Cancer Cells
Tamoxifen (TAM) is an antiestrogen widely used in the treatment of patients whose breast tumors express estrogen receptor alpha (ERα) Of the patients initially responsive to the therapy, 40% eventually become resistant antiestrogens. The mechanisms involved in TAM resistance (TAM-R) have yet to be fully ascertained. The orphan nuclear receptor Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) is down-regulated in TAMR breast cancer cell lines. When COUP-TFII expression is restored in TAM-R cells, cell proliferation is again TAM inhibited. The mechanism for COUP-TFII’s restoration of TAMsensitivity is unknown. Recently, COUP-TFII and nucleolin were shown to oimmunoprecipitate and colocalize in breast cancer cells and human breast tumors; nevertheless, the implications of this interaction are unknown. Nucleolin is primarily in nucleoli; however, it is in the cytoplasm and plasma membrane of cancer cells. Nucleolin acts in chromatin remodeling, rDNA transcription, rRNA maturation, ribosome assembly, and nucleo-cytoplasmic transport. The anticancer drug AS1411, a G-quartet aptamer, targets nucleolin. Thus, the focus of my research was to determine if AS1411 inhibited COUP-TFII-regulated endogenous gene transcription in breast cancer cells. COUP-TFII increased transcription of the tumor suppressor retinoic acid receptor β gene (RARβ) in breast cancer cells. I found that AS1411 inhibited COUP-TFII stimulated RARβ transcription in T47D ERα+ human breast cancer cells. These data indicate that nucleolin acts as a coactivator for COUP-TFII-regulation of RARβ gene transcription and offers a possible mechanism for COUP-TFII’s restoration of TAM-sensitivity, i.e., by increasing differentiation as indicated by an increase in RARβ tumor suppressor expression.