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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 under E2-depleted condition, Cyr61 is sufficient to induce MCF-7 cells grow in the absence of E2. MCF-7 cells transfected with Cyr61 (MCF-7/Cyr61) became E2-independent but still E2-responsive. On the other hand, MCF-7/vector cells 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. ERa expression in MCF-7/Cyr61 cells is decreased although still functional. Additionally, 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 anti-E2 resistance, and to promote invasiveness in vitro, and to inducemore » tumorigenesis in vivo, all of which are characteristics of an aggressive breast cancer phenotype.« less

Authors:
; ; ; ;
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE; National Institutes of Health Contract DK49049, Department of Defense Breast Cancer Research Program Postdoctoral Traineeship (US)
OSTI Identifier:
837722
Report Number(s):
LBNL-49521
R&D Project: 447401; TRN: US200506%%353
DOE Contract Number:
AC03-76SF00098
Resource Type:
Journal Article
Resource Relation:
Journal Name: Oncogene; Journal Volume: 21; Journal Issue: 53; Other Information: Submitted to Oncogene: Volume 21, No.53; Journal Publication Date: 11/21/2002; PBD: 16 Jan 2002
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; CARCINOMAS; ESTROGENS; GENES; GROWTH FACTORS; IN VITRO; IN VIVO; MAMMARY GLANDS; MICE; NEOPLASMS; PHENOTYPE

Citation Formats

Tsai, Miaw-Sheue, Bogart, Daphne F., Castaneda, Jessica M., Li, Patricia, and Lupu, Ruth. Cyr61 promotes breast tumorigenesis and cancer progression. United States: N. p., 2002. Web. doi:10.1038/sj.onc.1205682.
Tsai, Miaw-Sheue, Bogart, Daphne F., Castaneda, Jessica M., Li, Patricia, & Lupu, Ruth. Cyr61 promotes breast tumorigenesis and cancer progression. United States. doi:10.1038/sj.onc.1205682.
Tsai, Miaw-Sheue, Bogart, Daphne F., Castaneda, Jessica M., Li, Patricia, and Lupu, Ruth. 2002. "Cyr61 promotes breast tumorigenesis and cancer progression". United States. doi:10.1038/sj.onc.1205682. https://www.osti.gov/servlets/purl/837722.
@article{osti_837722,
title = {Cyr61 promotes breast tumorigenesis and cancer progression},
author = {Tsai, Miaw-Sheue and Bogart, Daphne F. and Castaneda, Jessica M. and Li, Patricia and Lupu, Ruth},
abstractNote = {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 under E2-depleted condition, Cyr61 is sufficient to induce MCF-7 cells grow in the absence of E2. MCF-7 cells transfected with Cyr61 (MCF-7/Cyr61) became E2-independent but still E2-responsive. On the other hand, MCF-7/vector cells 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. ERa expression in MCF-7/Cyr61 cells is decreased although still functional. Additionally, 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 anti-E2 resistance, and to promote invasiveness in vitro, and to induce tumorigenesis in vivo, all of which are characteristics of an aggressive breast cancer phenotype.},
doi = {10.1038/sj.onc.1205682},
journal = {Oncogene},
number = 53,
volume = 21,
place = {United States},
year = 2002,
month = 1
}
  • No abstract prepared.
  • Highlights: {yields} Hv1 is specifically expressed in highly metastatic human breast tumor tissues. {yields} Hv1 regulates breast cancer cytosolic pH. {yields} Hv1 acidifies extracellular milieu. {yields} Hv1 exacerbates the migratory ability of metastatic cells. -- Abstract: The newly discovered human voltage-gated proton channel Hv1 is essential for proton transfer, which contains a voltage sensor domain (VSD) without a pore domain. We report here for the first time that Hv1 is specifically expressed in the highly metastatic human breast tumor tissues, but not in poorly metastatic breast cancer tissues, detected by immunohistochemistry. Meanwhile, real-time RT-PCR and immunocytochemistry showed that the expressionmore » levels of Hv1 have significant differences among breast cancer cell lines, MCF-7, MDA-MB-231, MDA-MB-468, MDA-MB-453, T-47D and SK-BR-3, in which Hv1 is expressed at a high level in highly metastatic human breast cancer cell line MDA-MB-231, but at a very low level in poorly metastatic human breast cancer cell line MCF-7. Inhibition of Hv1 expression in the highly metastatic MDA-MB-231 cells by small interfering RNA (siRNA) significantly decreases the invasion and migration of the cells. The intracellular pH of MDA-MB-231 cells down-regulated Hv1 expression by siRNA is obviously decreased compared with MDA-MB-231 with the scrambled siRNA. The expression of matrix metalloproteinase-2 and gelatinase activity in MDA-MB-231 cells suppressed Hv1 by siRNA were reduced. Our results strongly suggest that Hv1 regulates breast cancer intracellular pH and exacerbates the migratory ability of metastatic cells.« less
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  • No abstract prepared.
  • No abstract prepared.