Journal Article

The p160 family coactivators regulate breast cancer cell proliferation and invasion through autocrine/paracrine activity of SDF-1α/CXCL12

Hiromitsu Kishimoto, Zhuo Wang, Poornima Bhat-Nakshatri, David Chang, Robert Clarke and Harikrishna Nakshatri

in Carcinogenesis

Volume 26, issue 10, pages 1706-1715
Published in print October 2005 | ISSN: 0143-3334
Published online May 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi137
The p160 family coactivators regulate breast cancer cell proliferation and invasion through autocrine/paracrine activity of SDF-1α/CXCL12

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Estrogen receptors (ERs) regulate the transcription of genes involved in breast cancer cell proliferation, invasion and metastasis. In addition to ligand concentration, phosphorylation and coactivator/corepressor levels control ER-dependent transcription. In this study, we used MCF-7 breast cancer sublines with variable levels of the steroid receptor coactivator 1 (SRC-1) to investigate the importance of coactivator levels in basal and estrogen-inducible expression of SDF-1α/CXCL12, cathepsin D and cMyc. Basal expression of SDF-1α and cMyc but not of cathepsin D was substantially lower in a MCF-7 subline lacking SRC-1 ((MCF-7/p2) compared with MCF-7 sublines expressing SRC-1 (MCF-7/p1 and LCC2). Although estrogen efficiently induced SDF-1α in MCF-7/p1 cells, very little induction of this gene was observed in MCF-7/p2 cells. The absence of SRC-1 had no effect on estrogen-inducible expression cMyc and cathepsin D suggesting that coactivator levels determine the expression of only a subset of estrogen-regulated genes. Introduction of SRC-1, SRC-2/TIF-2 or SRC-3/AIB1 increased basal expression of SDF-1α in MCF-7/p2 cells. Consistent with the role of SDF-1α in mediating estrogen-induced proliferation, estrogen failed to increase proliferation of MCF-7/p2 cells. In matrigel invasion assays, conditioned media from MCF-7/p1 but not MCF-7/p2 cells increased invasion of cancer cells expressing metastasis-associated genes and CXCR4, the receptor for SDF-1α. These results suggest that coactivators control SDF-1α expression, which mediates estrogen-induced proliferation and invasion through autocrine and paracrine mechanisms, respectively. These results also provide a molecular explanation for recent observations linking co-overexpression of coactivators and her2/neu with poor prognosis: coactivators increase SDF-1α expression whereas her2/neu stabilize CXCR4 protein.

Keywords: 4-HT, 4-hydroxytamoxifen; CAT, chloramphenicol acetyltransferase; CCS, charcoal/dextran-treated serum; E2, estradiol; ER, estrogen receptor; ERE, estrogen response element; FBS, fetal bovine serum; MEM, minimal essential medium; MMP, matrix metalloproteinase; MTT, methyl thiazolyl tetrazolium; NR, nuclear receptor; SDF-1α, stromal derived factor 1alpha; SRC-1, steroid receptor coactivator 1

Journal Article.  6675 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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