Downregulation of steroid receptor coactivator-2 modulates estrogen-responsive genes and stimulates proliferation of mcf-7 breast cancer cells.
The p160/Steroid Receptor Coactivators SRC-1, SRC-2/GRIP1, and SRC-3/AIB1 are important regulators of Estrogen Receptor alpha (ERα) activity. However, whereas the functions of SRC-1 and SRC-3 in breast tumourigenesis have been extensively studied, little is known about the role of SRC-2. Previously, we reported that activation of the cAMP-dependent protein kinase, PKA, facilitates ubiquitination and proteasomal degradation of SRC-2 which in turn leads to inhibition of SRC-2-coactivation of ERα and changed expression of the ERα target gene, pS2. Here we have characterized the global program of transcription in SRC-2-depleted MCF-7 breast cancer cells using short-hairpin RNA technology, and in MCF-7 cells exposed to PKA activating agents. In order to identify genes that may be regulated through PKA-induced downregulation of SRC-2, overlapping transcriptional targets in response to the respective treatments were characterized. Interestingly, we observed decreased expression of several breast cancer tumour suppressor genes (e.g., TAGLN, EGR1, BCL11b, CAV1) in response to both SRC-2 knockdown and PKA activation, whereas the expression of a number of other genes implicated in cancer progression (e.g., RET, BCAS1, TFF3, CXCR4, ADM) was increased. In line with this, knockdown of SRC-2 also stimulated proliferation of MCF-7 cells. Together, these results suggest that SRC-2 may have an antiproliferative function in breast cancer cells.
Department of Clinical Science, University of Bergen, Bergen, Norway.
Ingvild S
IS
Fenne
Thomas
T
Helland
Marianne H
MH
Flågeng
Simon N
SN
Dankel
Gunnar
G
Mellgren
Jørn V
JV
Sagen
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D061986:MCF-7 Cells; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics* / Q000378:metabolism*; D009857:Oncogenes / Q000235:genetics; D059748:Proteolysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics
D047628:Estrogen Receptor alpha; D051958:Nuclear Receptor Coactivator 2; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases