Abstract
We have shown that Cyr61, an angiogenic regulator, is overexpressed in invasive and metastatic human breast cancer cells and tumor biopsies. We have further demonstrated that Cyr61 promotes acquisition of estrogen-independence and anti-estrogen resistance in vivo in breast cancer cells. Moreover, we have demonstrated that Cyr61 induces tumor formation and tumor vascularization in vivo, events mediated through the activation of the MAPK and the Akt signaling pathways. Here we investigate how Cyr61 expression is regulated in both estrogen receptor (ER)-positive and ER-negative breast cancer cells. We demonstrate that Cyr61 mRNA and protein expression is inducible by estrogen and anti-estrogens in ER-positive breast cancer cells. We show that a labile protein as well as a negative regulator might be involved in Cyr61 expression in estrogen-dependent breast cancer cells. Other important regulators of Cyr61 expression in breast cancer cells that we found are the phorbol ester TPA, vitamin D, and retinoic acid. TPA causes positive regulation of Cyr61 expression in ER-positive MCF-7 cells. Vitamin D induces a transient stimulatory effect on Cyr61 gene expression. Lastly, retinoic acid has a negative effect on Cyr61 expression and downregulates its expression in MCF-7 cells. Interestingly, most of these effects are not seen in aggressive breast cancer cells that do not express ER and express high levels of Cyr61, such as the MDA-MB-231 cells. Our results are in agreement with our knowledge that Cyr61 promotes tumor growth, and that tumor-promoting agents have a positive impact on cells that express low levels of Cyr61, such as the ER-positive breast cancer cells; however, these agents have no significant effect on cells that express high levels of Cyr61. Our findings suggest an association between increased Cyr61 expression and an aggressive phenotype of breast cancer cells.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Calcitriol / pharmacology
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Cysteine-Rich Protein 61
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Drug Resistance
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Estradiol / analogs & derivatives*
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Estradiol / pharmacology
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Estrogen Receptor Modulators / pharmacology
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Estrogens
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Female
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Fulvestrant
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Gene Expression Regulation, Neoplastic* / drug effects
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Genes, Immediate-Early
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Growth Substances / biosynthesis
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Growth Substances / genetics
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Growth Substances / physiology*
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Humans
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Immediate-Early Proteins / biosynthesis
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / physiology*
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Intercellular Signaling Peptides and Proteins*
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Neoplasm Invasiveness / genetics*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Neoplasms, Hormone-Dependent / genetics
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Neoplasms, Hormone-Dependent / metabolism
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Neoplasms, Hormone-Dependent / pathology
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Phenotype
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Protein Structure, Tertiary
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
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Receptors, Estrogen / physiology*
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Selective Estrogen Receptor Modulators / pharmacology
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Tamoxifen / pharmacology
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Tetradecanoylphorbol Acetate / pharmacology
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Transcriptional Activation / drug effects
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Transfection
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Tretinoin / pharmacology
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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Tumor Cells, Cultured / pathology
Substances
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CCN1 protein, human
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Cysteine-Rich Protein 61
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Estrogen Receptor Modulators
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Estrogens
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Growth Substances
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Immediate-Early Proteins
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Intercellular Signaling Peptides and Proteins
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Neoplasm Proteins
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RNA, Messenger
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RNA, Neoplasm
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Receptors, Estrogen
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Selective Estrogen Receptor Modulators
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Tamoxifen
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Fulvestrant
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Estradiol
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Tretinoin
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Calcitriol
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Tetradecanoylphorbol Acetate