title: Cyr61 promotes breast tumorigenesis and cancer progression.
abstract: Cyr61, a member of the CCN family of genes, is an angiogenic factor. We have shown that it is overexpressed in invasive and metastatic human breast cancer cells and tissues. Here, we investigated whether Cyr61 is necessary and/or sufficient to bypass the 'normal' estrogen (E2) requirements for breast cancer cell growth. Our results demonstrate that Cyr61 is sufficient to induce MCF-7 cells to grow in the absence of E2. Cyr61-transfected MCF-7 cells (MCF-7/Cyr61) became E2-independent but still E2-responsive. On the other hand, MCF-7 cells transfected with the vector DNA (MCF-7/V) remain E2-dependent. MCF-7/Cyr61 cells acquire an antiestrogen-resistant phenotype, one of the most common clinical occurrences during breast cancer progression. MCF-7/Cyr61 cells are anchorage-independent and capable of forming Matrigel outgrowth patterns in the absence of E2. ER alpha expression in MCF-7/Cyr61 cells is decreased although still functional. Moreover, MCF-7/Cyr61 cells are tumorigenic in ovariectomized athymic nude mice. The tumors resemble human invasive carcinomas with increased vascularization and overexpression of vascular endothelial growth factor (VEGF). Our results demonstrate that Cyr61 is a tumor-promoting factor and a key regulator of breast cancer progression. This study provides evidence that Cyr61 is sufficient to induce E2-independence and antiestrogen-resistance, and to promote invasiveness in vitro, and to induce tumorigenesis in vivo, all of which are characteristics of an aggressive breast cancer phenotype.
authors.affiliation: Ernest Orlando Lawrence Berkeley National Laboratory, University of California, One Cyclotron Road, Berkeley, California, CA 94720, USA.
authors.forename: Miaw-Sheue
authors.initials: MS
authors.lastname: Tsai
authors.forename: Daphne F
authors.initials: DF
authors.lastname: Bogart
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Castañeda
authors.forename: Patricia
authors.initials: P
authors.lastname: Li
authors.forename: Ruth
authors.initials: R
authors.lastname: Lupu
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D003094:Collagen; D055515:Cysteine-Rich Protein 61; D018450:Disease Progression; D015536:Down-Regulation; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D004967:Estrogens; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007797:Laminin; D008222:Lymphokines / Q000096:biosynthesis; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology*; D011509:Proteoglycans; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D004338:Drug Combinations; D016228:Endothelial Growth Factors; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D004967:Estrogens; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin; D008222:Lymphokines; D009363:Neoplasm Proteins; D011509:Proteoglycans; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C059485:matrigel; D000077267:Fulvestrant; D004958:Estradiol; D003094:Collagen