Mitogenic Activity of Estrogens in Human Breast Cancer Cells Does Not Rely on Direct Induction of Mitogen-Activated Protein Kinase/Extracellularly Regulated Kinase or Phosphatidylinositol 3-Kinase

Gaben, Anne-Marie; Saucier, Cécile; Bedin, M; Redeuilh, Gérard; Mešter, Ján

doi:10.1210/me.2003-0133

Cited by 37 publications

(37 citation statements)

References 40 publications

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“…The nongenomic actions of estradiol include effects on calcium flux that occur rapidly without being mediated by transcriptional effects of nuclear ER (Nadal et al 2001, Song et al 2002, Gaben et al 2004. Based on the rapid activation of estrogen-induced MAPK phosphorylation including ERK, p38, and SAPK/JNK pathways, nongenomic effects should be involved in the signal activation in MCF-7 cells.…”

Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation

Takahashi¹,

Otsuka²,

Miyoshi³

et al. 2008

Journal of Endocrinology

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Estrogen is involved in the development and progression of breast cancer. Here, we investigated the effects of bone morphogenetic proteins (BMPs) on breast cancer cell proliferation caused by estrogen using human breast cancer MCF-7 cells. MCF-7 cells express estrogen receptors (ESR1 and ESR2), BMP receptors, and SMAD signaling molecules. Estradiol and membrane-impermeable estradiol stimulated MCF-7 cell proliferation. Estradiol also reduced mRNA levels of ESR1, aromatase, and steroid sulfatase. Treatment with BMPs and activin had no effects on MCF-7 cell proliferation. However, BMP2, BMP4, BMP6, BMP7, and activin suppressed estradiolinduced cell mitosis, with the effects of BMP6, BMP7, and activin being more prominent than those of BMP2 and BMP4. Activin decreased ESR1 mRNA expression, while BMP6 and BMP7 impaired steroid sulfatase expression in MCF-7 cells. Interestingly, SMAD1,5,8 activation elicited by BMP6 and BMP7, but not by BMP2 and BMP4, was preserved even under the exposure of a high concentration of estradiol. The difference of BMP responsiveness was likely due to the differential modulation of BMP receptor expression induced by estradiol. In this regard, estradiol decreased the expression levels of BMPR1A, BMPR1B, ACVR2A, and ACVR2B but did not affect ACVR1 and BMPRII, leading to the sustained effects of BMP6 and BMP7 in estrogen-treated MCF-7 cells. Estradiol rapidly activated MAPK phosphorylation including extracellular signal-regulated kinase 1/2, p38, and stress-activated protein kinase/c-Jun NH2-terminal kinase pathways and BMP6, BMP7, and activin preferentially inhibited estradiol-induced p38 phosphorylation. SB203580, a selective p38 MAPK inhibitor effectively suppressed estradiol-induced cell mitosis, suggesting that p38 MAPK plays a key role in estrogen-sensitive breast cancer cell proliferation. Thus, a novel interrelationship between estrogen and the breast cancer BMP system was uncovered, in which inhibitory effects of BMP6 and BMP7 on p38 signaling and steroid sulfatase expression were functionally involved in the suppression of estrogen-induced mitosis of breast cancer cells.

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Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation

Takahashi¹,

Otsuka²,

Miyoshi³

et al. 2008

Journal of Endocrinology

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“…Hiscox et al (26) also showed that in tamoxifen-resistant epidermal growth factor receptor overexpressing MCF-7 cells, the combination of AZD0530 and the epidermal growth factor receptor inhibitor gefitinib blocked migration and invasion in an additive manner. A number of studies have shown that inhibiting c-Src activity in breast cancer cells blocks estrogen-induced cell cycle progression and mitogenesis (33,34). Additionally, c-Src inhibitors have also been shown to block estrogen-induced migration in endometrial cells (35) and disrupt adherans junctions in endothelial cells (36).…”

Section: Discussionmentioning

confidence: 99%

Cooperative action of tamoxifen and c-Src inhibition in preventing the growth of estrogen receptor–positive human breast cancer cells

Herynk

Beyer

Cui

et al. 2006

Molecular Cancer Therapeutics

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It has long been appreciated that estrogenic signaling contributes to breast cancer progression. c-Src is also required for a number of processes involved in tumor progression and metastasis. We have previously identified the K303R mutant estrogen receptor A (ERA) that confers hypersensitivity to low levels of estrogen. Because ERA and c-Src have been shown to interact in a number of different systems, we wanted to evaluate the role of c-Src kinase in estrogen-stimulated growth and survival of ERA-positive breast cancer cells. MCF-7 cells stably expressing the mutant receptor showed increased c-Src kinase activity and c-Src tyrosine phosphorylation when compared with wild-type ERA-expressing cells. A c-Src inhibitor, AZD0530, was used to analyze the biological effects of pharmacologically inhibiting c-Src kinase activity. MCF-7 cells showed an anchoragedependent growth IC 50 of 0.47 Mmol/L, which was increased 4-fold in the presence of estrogen. In contrast, cells stably expressing the mutant ERA had an elevated IC 50 that was only increased 1.4-fold by estrogen stimulation. The c-Src inhibitor effectively inhibited the anchorage-independent growth of both of these cells, and estrogen was able to reverse these effects. When cells were treated with suboptimal concentrations of c-Src inhibitor and tamoxifen, synergistic inhibition was observed, suggesting a cooperative interaction between c-Src and ERA. These data clearly show an important role for ERA and estrogen signaling in c-Src -mediated breast cancer cell growth and survival. Here, we show that c-Src inhibition is blocked by estrogen signaling; thus, the therapeutic use of c-Src inhibitors may require inhibition of ERA in estrogen-dependent breast cancer.

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“…2A). This is not entirely surprising as other studies have suggested that E 2 can be mitogenic without detectable activation of ERK1/2 in MCF-7 cells (19,21).…”

Section: Discussionmentioning

confidence: 52%

“…For instance, Lewis et al have recently shown that PD98059 had no significant effect on E 2 -induced phosphorylation of activating transcription factor-2 (20). Other studies in which estrogendeprived cells were treated with E 2 reported no activation of the MEK/ERK pathway despite the stimulation of entry into cell cycle progression, and treatment of these cells with U0126 was only partially inhibitory on cell cycle progression (21). Similarly, Bonapace et al reported that treatment of MCF-7 cells with E 2 allowed the cells to overcome a G1 block induced by HMG-CoA reductase inhibitors and that this effect did not require activation of ERK1/2 (22).…”

Section: Introductionmentioning

confidence: 99%

MEK ablation in MCF-7 cells blocks DNA synthesis induced by serum, but not by estradiol or growth factors

Estes

Thottassery²,

Westbrook³

et al. 2006

Int J Oncol

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Abstract. The role of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling in estrogen receptor positive (ER + ) MCF-7 breast carcinoma cells is not well understood. We depleted MEK by cotransfection of MEK1 and MEK2 siRNA duplexes in a MCF-7 derived line (MCF-7/ lacZ, ML-20) and determined its effect on serum, 17ß-estradiol (E 2 ), and growth factor induced DNA synthesis. MEK knockdown did not decrease fetal bovine serum-induced DNA synthesis in ML-20 cells although it did inhibit DNA synthesis induced by estrogen-stripped calf serum (CCS) suggesting that MEK activation plays an important role in growth signaling induced by serum components other than estrogen. Consistent with this notion, MEK knockdown only modestly decreased DNA synthesis induced by E 2 -supplemented CCS medium in ML-20 cells. Similarly, MEK knockdown only caused moderate decreases in DNA synthesis induced by fibroblast growth factor-1 (FGF-1) or heregulin-ß1 (HRGß1) in this media. Also, there were only minimal effects of MEK knockdown in cells treated with growth factor-supplemented serum-free medium. Although MEK depletion inhibited ERK1/2 phosphorylation induced by CCS in these cells, that induced by growth factor supplemented CCS media was relatively unaffected. Similarly, ERK1/2 phosphorylation induced by growth factorsupplemented serum-free media was also relatively unaffected by MEK depletion. These results suggest that pathways regulating DNA synthesis induced by serum in MCF-7 cells are significantly more dependent on constitutive MEK levels than that induced by E 2 or growth factors.

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Mitogenic Activity of Estrogens in Human Breast Cancer Cells Does Not Rely on Direct Induction of Mitogen-Activated Protein Kinase/Extracellularly Regulated Kinase or Phosphatidylinositol 3-Kinase

Cited by 37 publications

References 40 publications

Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation

Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation

Cooperative action of tamoxifen and c-Src inhibition in preventing the growth of estrogen receptor–positive human breast cancer cells

MEK ablation in MCF-7 cells blocks DNA synthesis induced by serum, but not by estradiol or growth factors

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