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, Harikrishna Nakshatri

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)1706-1715
Number of pages10
JournalCarcinogenesis
Volume26
Issue number10
DOIs
StatePublished - Oct 2005

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Nuclear Receptor Coactivator 1
Estrogens
MCF-7 Cells
Cell Proliferation
Breast Neoplasms
Cathepsin D
Estrogen Receptors
Genes
CXCR4 Receptors
Neoplasm Metastasis
Co-Repressor Proteins
Conditioned Culture Medium
Phosphorylation
Ligands
Neoplasms
Proteins

ASJC Scopus subject areas

  • Cancer Research

Cite this

The p160 family coactivators regulate breast cancer cell proliferation and invasion through autocrine/paracrine activity of SDF-1α/CXCL12. / Kishimoto, Hiromitsu; Wang, Zhuo; Bhat-Nakshatri, Poornima; Chang, David; Clarke, Robert; Nakshatri, Harikrishna.

In: Carcinogenesis, Vol. 26, No. 10, 10.2005, p. 1706-1715.

Research output: Contribution to journalArticle

Kishimoto, Hiromitsu ; Wang, Zhuo ; Bhat-Nakshatri, Poornima ; Chang, David ; Clarke, Robert ; Nakshatri, Harikrishna. / The p160 family coactivators regulate breast cancer cell proliferation and invasion through autocrine/paracrine activity of SDF-1α/CXCL12. In: Carcinogenesis. 2005 ; Vol. 26, No. 10. pp. 1706-1715.
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AU - Clarke, Robert

AU - Nakshatri, Harikrishna

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AB - 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.

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