scholarly journals Estrogen Signaling via a Linear Pathway Involving Insulin-Like Growth Factor I Receptor, Matrix Metalloproteinases, and Epidermal Growth Factor Receptor to Activate Mitogen-Activated Protein Kinase in MCF-7 Breast Cancer Cells

Endocrinology ◽  
2007 ◽  
Vol 148 (8) ◽  
pp. 4091-4101 ◽  
Author(s):  
Robert X.-D. Song ◽  
Zhenguo Zhang ◽  
Yucai Chen ◽  
Yongde Bao ◽  
Richard J. Santen
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cell Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Mapk Activation ◽  
Igf I ◽  
Sequential Activation ◽  
Epidermal Growth ◽  
Mcf 7

We present an integrated model of an extranuclear, estrogen receptor-α (ERα)-mediated, rapid MAPK activation pathway in breast cancer cells. In noncancer cells, IGF-I initiates a linear process involving activation of the IGF-I receptor (IGF-IR) and matrix metalloproteinases (MMP), release of heparin-binding epidermal growth factor (HB-EGF), and activation of EGF receptor (EGFR)-dependent MAPK. 17β-Estradiol (E2) rapidly activates IGF-IR in breast cancer cells. We hypothesize that E2 induces a similar linear pathway involving IGF-IR, MMP, HB-EGF, EGFR, and MAPK. Using MCF-7 breast cancer cells, we for the first time demonstrated that a sequential activation of IGF-IR, MMP, and EGFR existed in E2 and IGF-I actions, which was supported by evidence that the selective inhibitors of IGF-IR and MMP or knockdown of IGF-IR all inhibited E2- or IGF-I-induced EGFR phosphorylation. Using the inhibitors and small inhibitory RNA strategies, we also demonstrated that the same sequential activation of the receptors occurred in E2-, IGF-I-, but not EGF-induced MAPK phosphorylation. Additionally, a HB-EGF neutralizing antibody significantly blocked E2-induced MAPK activation, further supporting our hypothesis. The biological effects of sequential activation of IGF-IR and EGFR on E2 stimulation of cell proliferation were also investigated. Knockdown or blockade of IGF-IR significantly inhibited E2- or IGF-I-stimulated but not EGF-induced cell growth. Knockdown or blockade of EGFR abrogated cell growth induced by E2, IGF-I, and EGF, indicating that EGFR is a downstream molecule of IGF-IR in E2 and IGF-I action. Together, our data support the novel view that E2 can activate a linear pathway involving the sequential activation of IGF-IR, MMP, HB-EGF, EGFR, and MAPK.

scholarly journals Analogs of GnRH-I and GnRH-II inhibit epidermal growth factor-induced signal transduction and resensitize resistant human breast cancer cells to 4OH-tamoxifen

2005 ◽  
Vol 153 (4) ◽  
pp. 613-625 ◽  
Author(s):  
Andreas R Günthert ◽  
Carsten Gründker ◽  
Agnes Olota ◽  
Julia Läsche ◽  
Nicola Eicke ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Antiproliferative Effects ◽  
Epidermal Growth ◽  
Mcf 7

About 50–64% of human breast cancers express receptors for GnRH-I. Direct antiproliferative effects of analogs of GnRH-I on human breast cancer cell lines have been shown. They are at least in part mediated by antagonizing growth promoting effects of estradiol, epidermal growth factor (EGF) or insulin-like growth factor. Recently, expression of a putative receptor for GnRH-II in human tissues was demonstrated. Antiproliferative effects of GnRH-II in human endometrial and ovarian cancer cells were shown not to be mediated through the GnRH-I receptor. Now we demonstrate direct anti-proliferative effects of the GnRH-I analog Triptorelin and the GnRH-II analog [d-Lys6]GnRH-II in MCF-7 and T47D human breast cancer cells expressing GnRH-I receptors and putative GnRH-II receptors. Pretreatment with Triptorelin or [d-Lys6]GnRH-II blocked EGF-induced autophosphoryla-tion of EGF receptor and activation of mitogen-activated protein kinase (extracellular-signal-regulated kinase 1/2 (ERK1/2)) in these cells. In sublines of MCF-7 and T47D cells, which were developed to be resistant to 4OH-tamoxifen, HER-2/p185 was overexpressed. Pretreatment of these cell lines with Triptorelin or [d-Lys6]GnRH-II completely abolished resistance to 4OH-tamoxifen, assessed by 4OH-tamoxifen-induced apoptosis. Analogs of GnRH-I and GnRH-II counteract EGF-dependent signal transduction in human breast cancer cells with expression of receptors for GnRH-I and GnRH-II. Through this mechanism, they probably reverse acquired resistance to 4OH-tamoxifen mediated through overexpression or activation of receptors of the c-erbB family.

INSULIN-LIKE GROWTH FACTOR TYPE I AND INSULIN-LIKE GROWTH FACTOR TYPE II STIMULATE OESTRADIOL-17β HYDROXYSTEROID DEHYDROGENASE (REDUCTIVE) ACTIVITY IN BREAST CANCER CELLS

1991 ◽  
Vol 129 (2) ◽  
pp. R5-R8 ◽  
Author(s):  
Anita Singh ◽  
M.J. Reed
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Hydroxysteroid Dehydrogenase ◽  
Type I ◽  
Insulin Like Growth Factor ◽  
Igf I ◽  
Factor Type ◽  
Mcf 7

ABSTRACT Oestradiol-17β hydroxysteroid dehydrogenase (E2DH) is present in normal and malignant breast tissues and also in cultured breast cancer cells. It can act in a reductive direction to convert oestrone to the biologically active oestrogen, oestradiol, or in an oxidative direction to metabolize oestradiol to oestrone and may therefore have a crucial role in regulating breast tissue concentrations of oestradiol. Insulin-like growth factor-type I (IGF-I) and IGF-II are both mitogens for breast cancer cells. In this study we have examined the effect of these growth factors on the reductive and oxidative activities of E2DH in MCF-7 (receptor positive) and MDA-MB-231 (receptor negative) breast cancer cells. Both IGF-I (80 ng/ml) and IGF-II (80 ng/ml) significantly stimulated E2DH reductive activity (up to 138%) in MCF-7 cells but had no effect on oxidative activity. Addition of IGF-II (100 ng/ml) to MDA-MB-231 cells resulted in a small but statistically significant (p<0.05) increase in E2DH reductive activity (18%) but in these cells reductive activity is 25-70 times lower than oxidative activity. If IGF-I and IGF-II act to stimulate E2DH reductive activity in breast tumours then such a mechanism could account for the increased concentrations of oestradiol detected in breast tumours.

scholarly journals Growth Factor-Induced Transcription via the Serum Response Element Is Inhibited by Cyclic Adenosine 3′,5′-Monophosphate in MCF-7 Breast Cancer Cells*

Endocrinology ◽  
1997 ◽  
Vol 138 (6) ◽  
pp. 2219-2226 ◽  
Author(s):  
William L. Lowe ◽  
Ronggen Fu ◽  
Michelle Banko
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cell Growth ◽  
Breast Cancer Cells ◽  
Intracellular Camp ◽  
Gene Treatment ◽  
Igf I ◽  
Erk Activity ◽  
Serum Response ◽  
Mcf 7

Abstract The effect of increased intracellular cAMP on MCF-7 breast cancer cell growth was examined by treating cells with either forskolin, an activator of adenylate cyclase, or 8-[4-chlorophenylthio]-cAMP (8-CPT-cAMP), a cAMP analog. Compared to cells maintained in control medium, treatment with either 1 or 10 μm forskolin decreased cell growth by 17% and 68%, respectively, whereas treatment with 250 μm 8-CPT-cAMP decreased cell growth by 29%. To determine whether this effect of cAMP on cell growth was mediated by inhibition of the activity of extracellular signal-regulated kinases 1 and 2 (ERK1 and -2), two mitogen-activated protein kinases, the effect of cAMP on growth factor-induced ERK activity in MCF-7 cells was examined. Treatment with either insulin-like growth factor I (IGF-I) or epidermal growth factor (EGF) for 10 min stimulated a 4- to 8-fold increase in ERK1 and -2 activity. This effect of IGF-I and EGF was not inhibited by increased intracellular cAMP generated by pretreatment of the cells with 10 μm forskolin. Similarly, 10μ m forskolin had no effect on IGF-I- or EGF-induced ERK activity in cells treated with growth factor for 30 min. To determine whether cAMP inhibits other growth factor-mediated effects, its effect on the activity of the serum response element (SRE), a DNA promoter element whose activity is regulated by a variety of growth-promoting events, was examined. For these assays, MCF-7 cells were transiently transfected with pTK81-SRE-Luc, a luciferase fusion gene that contains the SRE cloned 5′ to a minimal thymidine kinase promoter and the luciferase gene. Treatment with either IGF-I or EGF increased pTK81-SRE-Luc activity in a dose-dependent fashion. Pretreatment of cells with 10 μm forskolin decreased IGF-I- and EGF-stimulated luciferase activity by ∼75%. An intermediate effect was observed using 1 μm forskolin. When intracellular cAMP levels were increased using 8-CPT-cAMP, similar results were obtained. SRE activity is dependent upon the activation by phosphorylation of a ternary complex factor; included among the ternary complex factors is Elk-1. When MCF-7 cells were cotransfected with a vector that expresses a Gal4/Elk-1 fusion protein and UAS-TK-Luc, a plasmid that contains two Gal4 DNA recognition sites cloned 5′ to a thymidine kinase promoter and the luciferase gene, treatment with forskolin partially inhibited the activation of Elk-1 by IGF-I and EGF. These data demonstrate that in MCF-7 breast cancer cells, cAMP has no effect on IGF-I- or EGF-induced ERK activity, but it inhibits growth factor-induced transcription. Taken together with the effects of cAMP on IGF-I- and EGF-induced Elk-1 activation, these data suggest that the effect of cAMP on SRE activity occurs distal to ERK activation, possibly via inhibition of an ERK-independent pathway. Finally, these data indicate that the effect of increased intracellular cAMP on breast cancer growth may be mediated through inhibition of specific growth factor-induced effects, including gene transcription.

scholarly journals Role of Insulin-Like Growth Factor Binding Protein-3 in 1, 25-Dihydroxyvitamin-D3-Induced Breast Cancer Cell Apoptosis

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
C. Brosseau ◽  
G. Pirianov ◽  
K. W. Colston
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Igf I ◽  
Induced Apoptosis ◽  
Parp 1 ◽  
Mcf 7 ◽  
Igfbp 3

Insulin-like growth factor I (IGF-I) is implicated in breast cancer development and 1, 25-dihydroxyvitamin D3(1, 25-D3) has been shown to attenuate prosurvival effects of IGF-I on breast cancer cells. In this study the role of IGF binding protein-3 (IGFBP-3) in 1, 25-D3-induced apoptosis was investigated using parental MCF-7 breast cancer cells and MCF-7/VDRcells, which are resistant to the growth inhibitory effects of 1, 25-D3. Treatment with 1, 25-D3increased IGFBP-3 mRNA expression in both cell lines but increases in intracellular IGFBP-3 protein and its secretion were observed only in MCF-7. 1, 25-D3-induced apoptosis was not associated with activation of any caspase but PARP-1 cleavage was detected in parental cells. IGFBP-3 treatment alone produced cleavage of caspases 7, 8, and 9 and PARP-1 in MCF-7 cells. IGFBP-3 failed to activate caspases in MCF-7/VDRcells; however PARP-1 cleavage was detected. 1, 25-D3treatment inhibited IGF-I/Akt survival signalling in MCF-7 but not in MCF-7/VDRcells. In contrast, IGFBP-3 treatment was effective in inhibiting IGF-I/Akt pathways in both breast cancer lines. These results suggest a role for IGFBP-3 in 1, 25-D3apoptotic signalling and that impaired secretion of IGFBP-3 may be involved in acquired resistance to vitamin D in breast cancer.

scholarly journals Resveratrol Regulates Insulin-Like Growth Factor-II in Breast Cancer Cells

Endocrinology ◽  
2005 ◽  
Vol 146 (10) ◽  
pp. 4224-4233 ◽  
Author(s):  
Sharda Vyas ◽  
Yayesh Asmerom ◽  
Daisy D. De León
Keyword(s):  
Breast Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Hormonal Regulation ◽  
Breast Cancer Cells ◽  
Inhibitory Effect ◽  
T47d Cells ◽  
Igf I ◽  
17Β Estradiol ◽  
Mcf 7

IGF-II is a potent mitogen and inhibitor of apoptosis in breast cancer. Regulation of IGF-II is complex and includes inhibition by tumor suppressors, stimulation by oncogenes, and imprinting and hormonal regulation by estrogens. Resveratrol (RSV) is a phytoestrogen that displays estrogen-like agonistic and antagonistic activity. Recent studies have shown that RSV inhibits the growth of breast cancer cells and may represent a potent agent in chemopreventive therapy. Because 17β-estradiol regulates IGF-II, we hypothesized that RSV may have a similar effect on IGF-II. The present study was designed to examine whether: 1) RSV modulates IGF-II in breast cancer cells; 2) regulation of IGF-II by RSV is dependent on the ER status; and 3) IGF-II (not IGF-I) mediates RSV effects on breast cancer cells. Treatment of MCF-7 and T47D cells with RSV (10−6m) caused stimulation of precursor IGF-II mRNA and protein; this effect was blocked by coincubation with 17β-estradiol (10−9m). Cell growth stimulated by RSV (10−6m) was blocked by addition of a blocking IGF-I receptor antibody, or the antiestrogen tamoxifen (10−7m). In contrast, RSV treatment (10−4m) inhibited IGF-II secretion and cell growth in MCF-7 and T47D cells. No increase in IGF-II levels is seen in estrogen receptor (−) MCF-10 cells, even though cell growth was inhibited by RSV 10−4m and precursor IGF-II blocked the inhibitory effect of resveratrol. No change in IGF-I was observed with RSV treatment (10−6 to 10−4m). Our study demonstrates that RSV regulates IGF-II and that IGF-II mediates RSV effect on cell survival and growth in breast cancer cells.

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