Rapid actions of estrogensEstradiol modulates breast cancer cell apoptosis: a novel nongenomic steroid action relevant to carcinogenesis
Introduction
Several lines of evidence suggest that 17β-estradiol (E2) has a role in proliferation of different tumor cell types [1], [2], [3], [4]. This E2 effect appears to be mediated, at least partly, by a nongenomic mechanism of action, involving receptors localized at the cell membrane. Signal transduction from these receptors to intracellular effectors implies protein tyrosine kinase (PTK) activation [5]. PTKs are efficiently inhibited by the isoflavonoid genistein [6], which is one of the common dietary phytoestrogens [7]. The inhibition of the PTK-mediated pathway may thus contribute to the protective action of dietary phytoestrogens against breast cancer [8], which was demonstrated by a recent case-control study [9].
E2 may promote cancer cell growth and division by stimulating different effector systems. For instance, E2 has been shown to regulate the production of fibroblast growth factor 1 in normal and cancer breast cells [10], to activate proteins involved in the cell cycle control, such as G1 cyclins [11], [12], [13] and to stimulate expression of genes required for cell division such as the proto-oncogene c-myc [14]. However, little attention has been paid to the possibility that E2-activated signal transduction pathways may interact with those pathways controlling apoptosis (programmed cell death), although several studies did reveal positive and negative effects of steroids on apoptosis of noncancer cells [15], [16], [17].
Here we review the E2-activatable cell signaling events that are susceptible to modulating programmed cell death. We also present preliminary experimental data showing that E2 modulates spontaneous and VES-induced apoptosis in the human breast cancer-derived MCF-7 cell line.
Section snippets
Steroid-induced PTK activation
The possibility that steroids may act at the cell surface by stimulating protein tyrosine phosphorylation, similar to peptidic hormones and growth factors, has been suggested by the finding that antibody- [18] or ligand-induced [19] aggregation of progesterone-receptor complexes on the cell surface of human spermatozoa elicits a biological response (acrosome reaction). Ligand-induced receptor aggregation is a common characteristic of PTK-coupled receptors. Subsequently, a direct demonstration
From PTK to activator protein-1 family
The PTK primarily involved in the transduction of E2-generated signals in MCF-7 cells is c-src [5]. This is an interesting finding because c-src activation occurs in many human breast and colon cancers and is believed to be directly involved in tumorigenesis [28], [29]. In MCF-7 cells, E2-activated c-src phosphorylates two substrates, Shc and p190 [26], the former then associating to the GRB2/mSos complex and stimulating p21ras activation [30]. This leads to stimulation of a serine/threonine
From AP-1 family to apoptosis
c-Fos and c-jun are signal-transducing transcription factors of the AP-1 family, normally involved in the regulation of the cell cycle, cell differentiation and transformation. The implication of c-jun in the programmed cell death was suggested by different kinds of observation, including overexpression of c-jun in lymphoblastoid cell lines [36] and pheochromocytoma cells [37] undergoing apoptosis as a result of withdrawal of growth factors, sustained activation of c-jun accompanying apoptosis
Effects of E2 and E2-BSA on spontaneous and VES-induced apoptosis of MCF-7 cells
To test the hypothesis that E2 can modulate human breast cancer cell apoptosis, we performed experiments in which cells of the MCF-7 human breast cancer-derived cell line were exposed to E2 or its membrane-impermeant conjugate E2-BSA, added either alone or together with the known proapoptotic agent VES. MCF-7 cells, routinely grown in modified Eagle’s medium with Earle’s balanced salts enriched with 10% fetal bovine serum and equilibrated with 5% CO2 in air, were maintained for 1 week before
Conclusion
Steroids exert nongenomic effects, involving PTK stimulation, in many cell types. In many tumor-derived cell lines, E2 activates the src nonreceptor PTK, resulting in tyrosine phosphorylation of Shc and subsequent activation of the ras/MAP-kinase cascade. MAP kinase has recently been shown to activate expression of the members of AP-1 family c-fos and c-jun proto-oncogenes that subsequently can regulate the expression of caspases and other effectors of apoptosis. These findings make up a mosaic
References (45)
- et al.
Genistein, a specific inhibitor of tyrosine-specific protein kinases
J Biol Chem
(1987) - et al.
Phyto-oestrogens and breast cancer
Lancet
(1998) - et al.
Case-control study of phyto-estrogens and breast cancer
Lancet
(1997) - et al.
Production and oestrogen regulation of FGF1 in normal and cancer breast cells
Biochim Biophys Acta
(1998) - et al.
Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2
J Biol Chem
(1997) - et al.
17β-Estradiol inhibits apoptosis of endothelial cells
Biochem Biophys Res Commun
(1997) - et al.
Estrogens stimulate tamoxifen-induced neuronal cell apoptosis in vitroa possible nongenomic action
Biochem Biophys Res Commun
(1997) - et al.
Progesterone action through aggregation of a receptor on the sperm plasma membrane
FEBS Lett
(1992) - et al.
Insights into the function of a sperm-surface progesterone receptorevidence of ligand-induced receptor aggregation and the implication of proteolysis
Exp Cell Res
(1993) - et al.
Progesterone and 17α-hydroxyprogesterone
Novel stimulators of calcium influx in human sperm. J Biol Chem
(1990)
Analysis of pp60 c-src protein kinase activity in human tumor cell line and tissues
J Biol Chem
Rapid activation of MAP kinase by estrogen in the bone cell line
Biochem Biophys Res Commun
JnkA protein kinase stimulated by UV light and HA-Ras that binds and phosphorylates the c-Jun activation domain
Cell
The role of c-jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and γ radiation
J Biol Chem
A c-jun dominant negative mutant protects sympathetic neurons against programmed cell death
Neuron
Plasma membrane alterations and cytoskeletal changes in apoptosis
Exp Cell Res
Estradiol and progesterone receptors in malignant gastrointestinal tumors
Cancer Res
The role of estradiol receptor in the proliferative activity of vanadate on MCF-7 cells
Cell Growth Differ
Rapid membrane effects of steroids in neuroblastoma cellseffects of estrogen on mitogen activated protein kinase signalling cascade and c-fos immediate early gene transcription
Endocrinology
Immediate and transient stimulation of protein tyrosine phosphorylation by estradiol in MCF-7 cells
Oncogene
Phytoestrogens
J Clin Endocrinol Metab
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