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Phenotypic alterations in breast cancer cells overexpressing the nuclear receptor co-activator AIB1.

ABSTRACT: Estrogen signaling plays a critical role in a number of normal physiological processes and has important implications in the treatment of breast cancer. The p160 nuclear receptor coactivator, AIB1 (amplified in breast cancer 1), is frequently amplified and overexpressed in human breast cancer and has been shown to enhance estrogen-dependent transactivation.To better understand the molecular and physiological consequences of AIB1 overexpression in breast cancer cells, an AIB1 cDNA was transfected into the low AIB1 expressing, estrogen-receptor (ER) negative breast cancer cell line, MDA-MB-436. The features of a derivative cell line, designated 436.1, which expresses high levels of AIB1, are described and compared with the parental cell line.A significant increase in the levels of CREB binding protein (CBP) was observed in 436.1 cells and immunofluorescent staining revealed altered AIB1 and CBP staining patterns compared to the parental cells. Further, transient transfection assays demonstrated that the overall estrogen-dependent transactivation in 436.1 cells is approximately 20-fold higher than the parental cells and the estrogen dose-response curve is repositioned to the right. Finally, cDNA microarray analysis of approximately 7,100 cDNAs identified a number of differentially expressed genes in the 436.1 cells.These observations lend insight into downstream signaling pathways that are influenced by AIB1.

SUBMITTER: Anzick SL

PROVIDER: S-EPMC201023 | biostudies-literature | 2003 Sep

REPOSITORIES: biostudies-literature

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Phenotypic alterations in breast cancer cells overexpressing the nuclear receptor co-activator AIB1.

Anzick Sarah L SL Azorsa David O DO Simons S Stoney SS Meltzer Paul S PS

BMC cancer 20030910

<h4>Background</h4>Estrogen signaling plays a critical role in a number of normal physiological processes and has important implications in the treatment of breast cancer. The p160 nuclear receptor coactivator, AIB1 (amplified in breast cancer 1), is frequently amplified and overexpressed in human breast cancer and has been shown to enhance estrogen-dependent transactivation.<h4>Methods</h4>To better understand the molecular and physiological consequences of AIB1 overexpression in breast cancer ...[more]

PMID: 12964942

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Project description:BACKGROUND: The placenta-specific 1 (PLAC1) gene encodes a membrane-associated protein which is selectively expressed in the placental syncytiotrophoblast and in murine fetal tissues during embryonic development. In contrast to its transcriptional repression in all other adult normal tissues, PLAC1 is frequently activated and highly expressed in a variety of human cancers, in particular breast cancer, where it associates with estrogen receptor ? (ER?) positivity. In a previous study, we showed that ER?-signaling in breast cancer cells transactivates PLAC1 expression in a non-classical pathway. As the members of the p160/nuclear receptor co-activator (NCOA) family, NCOA1, NCOA2 and NCOA3 are known to be overexpressed in breast cancer and essentially involved in estrogen-mediated cancer cell proliferation we asked if these proteins are involved in the ER?-mediated transactivation of PLAC1 in breast cancer cells. METHODS: Applying quantitative real-time RT-PCR (qRT-PCR), Western Blot analysis and chromatin immunoprecipitation, we analyzed the involvement of NCOA1, NCOA2, NCOA3 in the ER?-mediated transactivation of PLAC1 in the breast cancer cell lines MCF-7 and SK-BR-3. RNAi-mediated silencing of NCOA3, qRT-PCR, Western blot analysis and ER? activation assays were used to examine the role of NCOA3 in the ER?-mediated regulation of PLAC1 in further detail. Transcript expression of NCOA3 and PLAC1 in 48 human breast cancer samples was examined by qRT-PCR and statistical analysis was performed using Student's t-test. RESULTS: We detected selective recruitment of NCOA3 but not NCOA1 or NCOA2 to the PLAC1 promoter only in ER?-positive MCF-7 cells but not in ER?-negative SK-BR-3 breast cancer cells. In addition, we demonstrate that silencing of NCOA3 results in a remarkable decrease of PLAC1 expression levels in MCF-7 cells which cannot be restored by treatment with estradiol (E?). Moreover, significant higher transcript levels of PLAC1 were found only in ER?-positive human breast cancer samples which also show a NCOA3 overexpression. CONCLUSIONS: In this study, we identified NCOA3 as a selective co-activator of ER?-mediated transactivation of PLAC1 in MCF-7 breast cancer cells. Our data introduce PLAC1 as novel target gene of NCOA3 in breast cancer, supporting the important role of both factors in breast cancer biology.

Dataset Information

Phenotypic alterations in breast cancer cells overexpressing the nuclear receptor co-activator AIB1.

Publications

Phenotypic alterations in breast cancer cells overexpressing the nuclear receptor co-activator AIB1.

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