Membrane-associated binding sites for estrogen contribute to growth regulation of human breast cancer cells

Márquez, Diana C.; Pietras, Richard J.

doi:10.1038/sj.onc.1204729

Cited by 157 publications

(122 citation statements)

References 56 publications

(78 reference statements)

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“…On the other hand, we cannot formally exclude the possibility that E 2 may activate immediate release of IGF-1 (or other growth factors) from an inactive storage form(s), as recently documented (Filardo et al, 2000) for epidermal growth factor. The nongenomic signaling of E 2 is postulated to be mediated by membrane-associated ER (Kelly and Levin, 2001), and this hypothesis is further supported by the recent demonstrations of membrane located ER␣ in MCF7 and other cell types (Marquez and Pietras, 2001;Powell et al, 2001). According to these studies, the fraction of plasma membrane-bound ER␣ ranged from 3 to 20% of the total in MCF7 cells.…”

Section: Interaction and Regulation Of The Estradiol-induced Signalsupporting

confidence: 56%

Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

Fernando

Wimalasena

2004

MBoC

113

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Estrogens such as 17-β estradiol (E2) play a critical role in sporadic breast cancer progression and decrease apoptosis in breast cancer cells. Our studies using estrogen receptor-positive MCF7 cells show that E2 abrogates apoptosis possibly through phosphorylation/inactivation of the proapoptotic protein BAD, which was rapidly phosphorylated at S112 and S136. Inhibition of BAD protein expression with specific antisense oligonucleotides reduced the effectiveness of tumor necrosis factor-α, H2O2, and serum starvation in causing apoptosis. Furthermore, the ability of E2 to prevent tumor necrosis factor-α-induced apoptosis was blocked by overexpression of the BAD S112A/S136A mutant but not the wild-type BAD. BAD S112A/S136A, which lacks phosphorylation sites for p90RSK1 and Akt, was not phosphorylated in response to E2 in vitro. E2 treatment rapidly activated phosphatidylinositol 3-kinase (PI-3K)/Akt and p90RSK1 to an extent similar to insulin-like growth factor-1 treatment. In agreement with p90RSK1 activation, E2 also rapidly activated extracellular signal-regulated kinase, and this activity was down-regulated by chemical and biological inhibition of PI-3K suggestive of cross talk between signaling pathways responding to E2. Dominant negative Ras blocked E2-induced BAD phosphorylation and the Raf-activator RasV12T35S induced BAD phosphorylation as well as enhanced E2-induced phosphorylation at S112. Chemical inhibition of PI-3K and mitogen-activated protein kinase kinase 1 inhibited E2-induced BAD phosphorylation at S112 and S136 and expression of dominant negative Ras-induced apoptosis in proliferating cells. Together, these data demonstrate a new nongenomic mechanism by which E2 prevents apoptosis.

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Section: Interaction and Regulation Of The Estradiol-induced Signalsupporting

confidence: 56%

Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

Fernando

Wimalasena

2004

MBoC

113

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“…In an earlier work, ϳ20% of E2 binding sites have been observed in the plasma membrane of MCF-7 cells, and the other sites include the nucleus (45%), cytosol (10%), and other organelles (2). In addition, membrane-impermeable conjugates of E2 and bovine serum albumin (E2-BSA) have evoked downstream signals, including the Src activation likewise membrane-permeable E2 (21,22).…”

Section: Discussionmentioning

confidence: 99%

“…Besides traditional genomic pathways of sex steroid receptors in the nucleus, the extranuclear non-genomic pathways of these receptors are being revealed to strongly relate to many biological consequences, including vascular protection and cell proliferation (1)(2)(3). These non-genomic pathways are rapidly mediated through several critical protein kinases.…”

mentioning

confidence: 99%

Epidermal Growth Factor Directs Sex-specific Steroid Signaling through Src Activation

Hitosugi¹,

Sasaki²,

Sato

et al. 2007

Journal of Biological Chemistry

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Estrogens and androgens exert many biological effects that do not require interactions of their receptors with chromosomal DNA. However, it has been a long-standing question how the sex steroid receptors provoke signal transduction outside the nucleus. Here we have shown that epidermal growth factor (EGF) directs sex-specific steroid signaling through Src activation. We have revealed that estrogen (E2)-induced Src activation takes place in, not only plasma, but also endomembranes. This was found ascribed to the existence of EGF and the occurrence of EGF receptor (EGFR)-involved endocytosis of estrogen receptor together with Src. EGFR, estrogen receptor, and Src were found to form a complex upon E2 stimulation. The cell growth of breast cancer-derived MCF-7 cells was found to remarkably increase through the above EGF-involved estrogen-signaling process. In contrast, the androgen 5␣-dihydrotestosterone-induced Src activation occurs only in the plasma membrane free from the interaction of EGFR with androgen receptor, irrespective of EGF. The cell growth occurred only moderately as a result. The spatial difference in Src activation between E2 and 5␣-dihydrotestosterone may be responsible for the different extent of observed cell growth.Besides traditional genomic pathways of sex steroid receptors in the nucleus, the extranuclear non-genomic pathways of these receptors are being revealed to strongly relate to many biological consequences, including vascular protection and cell proliferation (1-3). These non-genomic pathways are rapidly mediated through several critical protein kinases. A non-receptor protein tyrosine kinase, Src, is known to be activated immediately after a steroid stimulation (4, 5). This activated Src phosphorylates a wide variety of substrate proteins (such as Shc), which finally induce gene transcription (6, 7). In previous studies, the rapid activation of Src and other kinases by steroids has never been demonstrated in living cells.To answer the question about how the Src activity is nongenomically regulated by steroid receptors in single living cells, we developed a fluorescent indicator for Src kinase activity, and named it Srcus. This indicator can monitor substrate phosphorylation by activated endogenous Src as a fluorescent resonance energy transfer (FRET) 5 response in single living cells. Based on the fluorescence imaging with the present fluorescent indicators, we demonstrated that E2-induced Src activation takes place in not only plasma but also endomembranes. This was found ascribed to the existence of epidermal growth factor (EGF) and the occurrence of EGF receptor (EGFR)-involved endocytosis of estrogen receptor (ER) together with Src. EGFR, ER, and Src were found to form a complex upon E2 stimulation. The cell growth of breast cancer-derived MCF-7 cells was found to remarkably increase through the above EGF-involved estrogen-signaling process. In contrast to estrogen-activated Src signaling, the male steroid hormone 5␣-dihydrotestosterone (DHT) was found to activate Src only in th...

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“…9,10 ERa, in addition to its nuclear role as a transcription factor, is involved in regulating the PI3K pathway, which controls cell growth, proliferation and apoptosis. [11][12][13] In MCF-7 cells, RES induced a biphasic pattern of PI3K activity that increased at low concentrations and decreased at high concentrations. Activation of downstream PI3K effectors PKB/AKT and GSK-3 closely followed the pattern of PI3K activity.…”

mentioning

confidence: 99%

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Pozo‐Guisado

Merino

Mulero‐Navarro

et al. 2005

Intl Journal of Cancer

205

143

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Resveratrol (RES), a chemopreventive molecule, inhibits the proliferation of tumor cells of different etiologies. We previously showed that RES alters the cell cycle and induces apoptosis in MCF-7 breast tumor cells by interfering with the estrogen receptor (ERa)-dependent phosphoinositide 3-kinase (PI3K) pathway. Here, we analyzed signaling downstream of PI3K, to understand the mechanisms of RES-induced apoptosis. Apoptotic death by RES in MCF-7 was mediated by Bcl-2 downregulation since overexpression of this protein abolished apoptosis. Decreased Bcl-2 levels were not related to cytochrome c release, activation of caspases 3/8 or poly(ADP-ribose) polymerase proteolysis. However, RES decreased mitochondrial membrane potential and increased reactive oxygen species and nitric oxide production. NF-kB, a regulator of Bcl-2 expression, and calpain protease activity, a regulator of NF-kB, were both inhibited by RES. The patterns for NFkB and calpain activities followed that of PI3K and were inhibited by LY294002. NF-kB inhibition coincided with diminished MMP-9 activity and cell migration. These data suggest that RES-induced apoptosis in MCF-7 could involve an oxidative, caspase-independent mechanism, whereby inhibition of PI3K signaling converges to Bcl-2 through NF-kB and calpain protease activity. Therefore, Bcl-2 and NF-kB could be considered potential targets for the chemopreventive activity of RES in estrogen-responsive tumor cells. ' 2005 Wiley-Liss, Inc.Key words: resveratrol; caspase; Bcl-2; NF-kB; apoptosis Among natural compounds with beneficial effects on human health, RES (3,4 0 ,5-trihydroxystilbene) has attracted considerable interest. This molecule, present at relevant concentrations in red wine, 1 has been associated with a lower incidence of cardiovascular disease. Different studies have also suggested a beneficial effect of RES in cancer since it inhibits proliferation and promotes death in tumor cell lines of different origins, 2-4 and, in vivo, suppresses the formation of skin 5 and mammary gland 6 tumors in rodent models of carcinogenesis.We, as well as other laboratories, have found that the ability of RES to inhibit cell viability and proliferation in the human breast cancer cell lines MCF-7 and MDA-MB-231 was unrelated to ERa status. 7,8 However, apoptotic cell death was present only in ERapositive MCF-7 and involved cell-specific regulation of the G 1 /S and G 2 /M transitions of the cell cycle. 2,8 RES properties are related to ERa since this compound has estrogenic or antiestrogenic activities depending on its concentration and the phenotype of the target cell. 9,10 ERa, in addition to its nuclear role as a transcription factor, is involved in regulating the PI3K pathway, which controls cell growth, proliferation and apoptosis. [11][12][13] In MCF-7 cells, RES induced a biphasic pattern of PI3K activity that increased at low concentrations and decreased at high concentrations. Activation of downstream PI3K effectors PKB/AKT and GSK-3 closely followed the pattern of PI3K activity. 14 The ...

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Membrane-associated binding sites for estrogen contribute to growth regulation of human breast cancer cells

Cited by 157 publications

References 56 publications

Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

Epidermal Growth Factor Directs Sex-specific Steroid Signaling through Src Activation

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

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