Steroid Receptor Coactivator-3 and Activator Protein-1 Coordinately Regulate the Transcription of Components of the Insulin-Like Growth Factor/AKT Signaling Pathway

Abstract

Steroid receptor coactivator (SRC)-3, also called amplified in breast cancer 1, is a member of the p160 nuclear receptor coactivator family involved in transcriptional regulation of target genes. SRC-3 is frequently amplified and/or overexpressed in hormone-sensitive and hormone-insensitive tumors. We reported previously that SRC-3 stimulated prostate cell growth in a hormone-independent manner through activation of AKT signaling pathway. However, the underlying mechanism remains undefined. Here, we exploited the mifepristone-induced SRC-3 LNCaP prostate cancer cell line generated in our laboratory to identify SRC-3-regulated genes by oligonucleotide microarray analysis. We found that SRC-3 up-regulates the expression of multiple genes in the insulin-like growth factor (IGF)/AKT signaling pathway that are involved in cell proliferation and survival. In contrast, knockdown of SRC-3 in PC3 (androgen receptor negative) prostate cancer cells and MCF-7 breast cancer cells reduces their expression. Similarly, in prostate glands of SRC-3 null mice, expressions of these components in the IGF/AKT signal pathway are also reduced. Chromatin immunoprecipitation assay revealed that SRC-3 was directly recruited to the promoters of these genes, indicating that they are direct targets of SRC-3. Interestingly, we showed that recruitment of SRC-3 to two target promoters, IRS-2 and IGF-I, requires transcription factor activator protein-1 (AP-1). Taken together, our results clearly show that SRC-3 and AP-1 can coordinately regulate the transcription of multiple components in the IGF/AKT pathway to ensure ligand-independent cell proliferation and survival of cancer cells. (Cancer Res 2006; 66(22): 11039-46)

Epidermal Growth Factor Receptor Tyrosine Phosphorylation and Signaling Controlled by a Nuclear Receptor Coactivator, Amplified in Breast Cancer 1

“…AIB1 small interfering RNA (siRNA) oligonucleotides targeting different regions of AIB1 mRNA were synthesized by Qiagen. The AIB1 (1) siRNA target sequence is 5 ¶-AAAGA-CTCCTTAGGACCGCTT-3 ¶ (14), and the AIB1 (2) siRNA target sequence is 5 ¶-GGTGAATCGAGACGGAAAC-3 ¶ (12). The control siRNA used in the experiments is a scrambled sequence (5 ¶-AAUUCUCCGAACGUGUCACGUdTdT-3 ¶).…”

Overexpression of transcriptional coactivator AIB1 promotes hepatocellular carcinoma progression by enhancing cell proliferation and invasiveness

“…These results substantiate the promoting effect of AIB1 on HCC cell cycle progression. Downregulation of AIB1 is frequently associated with inhibition of Akt signaling (Zhou et al, 2003;Oh et al, 2004;Yan et al, 2006), and inhibition of Akt signaling can lead to upregulation of the CDK inhibitor p21…”

The steroid receptor coactivator-3 is a tumor promoter in a mouse model of thyroid cancer

“…However, it has become increasingly apparent that the functions of SRC-3 are not limited to acting as a transcription coactivator of liganded nuclear receptors (Torres-Arzayus et al, 2004;Zhou et al, 2005;Yan et al, 2006b). For example, it was shown that prostate cancer cell proliferation requires SRC-3 for transitioning cells from the G 1 /G 0 phase to the S phase (Zhou et al, 2005).…”

“…To understand the mechanism underlying the increased apoptotic activity in tumor cells deficient in SRC-3, we evaluated the expression of the proapoptotic gene, caspase-3 as well as the antiapoptotic gene, Bcl-2, in the thyroid of TRb PV/PV mice with or without SRC-3 by real-time reverse transcription-PCR ( Figure 4B) and western blot analysis ( Figure 4C). These two genes have been shown to be negatively or positively regulated by SRC-3 (Zhou et al, 2005;Yan et al, 2006b), respectively. Analysis by real-time RT-PCR indicates that the mRNA level of Bcl-2 was repressed by 31% in tumor cells deficient in SRC-3 (Figure 4Ba, compare bar 2 with 1).…”