The membrane estrogen receptor GPR30 mediates cadmium-induced proliferation of breast cancer cells

Journal Article · Sat May 15 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

OSTI ID:21344950

Xinyuan, Yu ^[1]; Filardo, Edward J ^[2]

---

1. Department of Biomedical and Pharmaceutical Sciences, and Center for Molecular Toxicology, 41 Lower College Road, College of Pharmacy, University of Rhode Island, Kingston, RI 02881 (United States)
2. Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, RI 02903 (United States)

Cadmium (Cd) is a nonessential metal that is dispersed throughout the environment. It is an endocrine-disrupting element which mimics estrogen, binds to estrogen receptor alpha (ERalpha), and promotes cell proliferation in breast cancer cells. We have previously published that Cd promotes activation of the extracellular regulated kinases, erk-1 and -2 in both ER-positive and ER-negative human breast cancer cells, suggesting that this estrogen-like effect of Cd is not associated with the ER. Here, we have investigated whether the newly appreciated transmembrane estrogen receptor, G-protein coupled receptor 30 (GPR30), may be involved in Cd-induced cell proliferation. Towards this end, we compared the effects of Cd in ER-negative human SKBR3 breast cancer cells in which endogenous GPR30 signaling was selectively inhibited using a GPR30 interfering mutant. We found that Cd concentrations from 50 to 500 nM induced a proliferative response in control vector-transfected SKBR3 cells but not in SKBR3 cells stably expressing interfering mutant. Similarly, intracellular cAMP levels increased about 2.4-fold in the vector transfectants but not in cells in which GPR30 was inactivated within 2.5 min after treatment with 500 nM Cd. Furthermore, Cd treatment rapidly activated (within 2.5 min) raf-1, mitogen-activated protein kinase kinase, mek-1, extracellular signal regulated kinases, erk-1/2, ribosomal S6 kinase, rsk, and E-26 like protein kinase, elk, about 4-fold in vector transfectants. In contrast, the activation of these signaling molecules in SKBR3 cells expressing the GPR30 mutant was only about 1.4-fold. These results demonstrate that Cd-induced breast cancer cell proliferation occurs through GPR30-mediated activation in a manner that is similar to that achieved by estrogen in these cells.

• OSTI ID: 21344950
• Journal Information: Toxicology and Applied Pharmacology, Vol. 245, Issue 1; Other Information: DOI: 10.1016/j.taap.2010.02.005; PII: S0041-008X(10)00049-9; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AMP
CADMIUM
CELL PROLIFERATION
ESTRADIOL
GTP-ASES
MAMMARY GLANDS
MEMBRANES
MUTANTS
NEOPLASMS
PHOSPHOTRANSFERASES
RECEPTORS
TOXICITY
VECTORS
WOMEN
ACID ANHYDRASES
ANIMALS
BODY
DISEASES
ELEMENTS
ENZYMES
ESTRANES
ESTROGENS
FEMALES
GLANDS
HORMONES
HYDROLASES
HYDROXY COMPOUNDS
MAMMALS
MAN
MEMBRANE PROTEINS
METALS
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANS
PHOSPHORUS-GROUP TRANSFERASES
PRIMATES
PROTEINS
STEROID HORMONES
STEROIDS
TENSORS
TRANSFERASES
VERTEBRATES