Up-regulation of PI3K/Akt signaling by 17β-estradiol through activation of estrogen receptor-α, but not estrogen receptor-β, and stimulates cell growth in breast cancer cells

Lee, Young‐Rae; Park, Jinny; Yu, Hong‐Nu; Kim, Jong‐Suk; Youn, Hyun Jo; Jung, Sung Hoo

doi:10.1016/j.bbrc.2005.08.256

Cited by 113 publications

(70 citation statements)

References 23 publications

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“…PI3K/Akt pathway is another signaling event regulated by estrogen-induced ROS. Activation of Akt by E2 or 4-OHE2 is either ER-independent or dependent (104,105). The exact mechanism of estrogen-mediated Akt activation is unclear; however, it is possible that the reversible inactivation of Cdc25A or PTEN by estrogen-induced ROS plays a key role in the activation of Akt.…”

Section: Ros-mediated Redox Signalingsmentioning

confidence: 99%

Dual roles of estrogen metabolism in mammary carcinogenesis

Chang

2011

BMB Reports

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A female hormone, estrogen, is linked to breast cancer incidence. Estrogens undergo phase I and II metabolism by which they are biotransformed into genotoxic catechol estrogen metabolites and conjugate metabolites are produced for excretion or accumulation. The molecular mechanisms underlying estrogen-mediated mammary carcinogenesis remain unclear. Cell proliferation through activation of estrogen receptor (ER) by its agonist ligands and is clearly considered as one of carcinogenic mechanisms. Recent studies have proposed that reactive oxygen species generated from estrogen or estrogen metabolites are attributed to genotoxic effects and signal transduction through influencing redox sensitive transcription factors resulting in cell transformation, cell cycle, migration, and invasion of the breast cancer. Conjuguation metabolic pathway is thought to protect cells from genotoxic and cytotoxic effects by catechol estrogen metabolites. However, methoxylated catechol estrogens have been shown to induce ER-mediated signaling pathways, implying that conjugation is not a simply detoxification pathway. Dual action of catechol estrogen metabolites in mammary carcinogenesis as the ER-signaling molecules and chemical carcinogen will be discussed in this review. [BMB reports 2011; 44(7): 423-434]

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Section: Ros-mediated Redox Signalingsmentioning

confidence: 99%

Dual roles of estrogen metabolism in mammary carcinogenesis

Chang

2011

BMB Reports

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“…ERα and ERβ are detectable in membrane fractions of breast cancer cells [46] and by immunohistochemistry (IHC) in breast tumor samples within and outside the nucleus [47]. In ER+ MCF7 cells, E2 increases ERα association with c-Src, Shc, and the IGF-1 receptor, ERα-dependent PI3 kinase activation, and proliferation [48][49][50]. Both ER subtypes can signal via nongenomic pathways, but cell context, including levels of ER expression or stoichiometry between signaling molecules, may be crucial.…”

Section: Crosstalk With Growth Factors and "Nongenomic" E2 Responsesmentioning

confidence: 99%

ERβ in breast cancer—Onlooker, passive player, or active protector?

2008

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The role of estrogen exposure in breast cancer risk is well-documented, and both estrogen synthesis and actions through the estrogen receptor (ER) have been targeted by therapies to control hormonedependent breast cancer. The discovery of a second ER form and its therapeutic implications sparked great interest. Both the original ERα and the more recently identified ERβ subtypes bind and respond similarly to many physiological and pharmacological ligands. However, differences in phytoestrogen binding have been noted, and subtype-specific ligands have been developed. Cell-based assays show that ERβ and its variants are generally less active on gene transcription than ERα, and may influence ERα activity; however, both gene-and cell-specific responses occur, and nongenomic activities are less well explored. Specific ligands, and methods to disrupt or eliminate receptor subtype expression in animal and cell models, demonstrate that the ERs have both overlapping and distinct biological functions. Overall, in cell-based studies, ERα appears to play a predominant role in cell proliferation, and ERβ is suggested to be antiproliferative.The potential for distinct populations of breast tumors to be identified based on ER subtype expression, and to exhibit distinct clinical behaviors, is of greatest interest. Several studies suggest that the majority of ER-positive tumors contain both subtypes, but that some tumors contain only ERβ and may have distinct clinical behaviors and responses. Expression of ERβ together with ERα favors positive responses to endocrine therapy in most studies, and additional studies to determine if the addition of ERβ to ERα as a tumor marker is of clinical benefit are warranted. In contrast, the positive association between ERβ and HER2 expression in high-grade ERα-negative breast cancer does not favor positive responses to endocrine therapy. Expression of ERβ in specific clinical subpopulations, and the potential for therapies targeting ERβ specifically, is discussed.

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“…The increased expression and activation of these intermediary molecules enhance the transcription of genes such as cyclin D1 that facilitate the entry of the cell into the cell cycle (14). Estrogen-induced increases in IGF-I expression result in the activation of the phosphoinositide-3-kinase pathway and Akt, thereby promoting cell survival through inhibition of downstream apoptotic pathways (15).…”

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confidence: 99%

Overexpression of the Insulin-Like Growth Factor I Receptor and Activation of the AKT Pathway in Hyperplastic Endometrium

McCampbell

Broaddus

Loose

et al. 2006

Clinical Cancer Research

119

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Purpose: Although there is considerable information on the molecular aberrations associated with endometrial cancer, very little is known of the changes in gene expression associated with endometrial hyperplasia. Experimental Design: To address this, we have compared the level of expression of estrogenregulated genes and components of the insulin-like growth factor I (IGF-I) signaling pathway in endometrial biopsies from subjects with normal endometrium, complex atypical endometrial hyperplasia, and endometrial adenocarcinoma (type I).Results: There was a significant increase in the expression of the IGF-I receptor (IGF-IR) in biopsies from hyperplastic endometrium and endometrial carcinoma compared with the proliferative endometrium. The receptor was also activated, as judged by increased tyrosine phosphorylation. In addition, in endometrial hyperplasia and carcinoma, the downstream components of the IGF-IR pathway are activated, as reflected in increased Akt phosphorylation. Loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression in endometrial hyperplasia did not correlate with increased activation of IGF-IR. However, the simultaneous loss of PTEN expression and increased IGF-IR activation in hyperplasia was associated with an increased incidence of endometrial carcinoma. Conclusions: These results suggest that up-regulation of IGF-IR and loss of PTEN may be independent events that give rise to complementary activation of the IGF-I pathway and increase the probability of the development of cancer. These studies suggest that increased expression of IGF-IR may be an important contributor to the risk of endometrial hyperplasia and cancer.

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Up-regulation of PI3K/Akt signaling by 17β-estradiol through activation of estrogen receptor-α, but not estrogen receptor-β, and stimulates cell growth in breast cancer cells

Cited by 113 publications

References 23 publications

Dual roles of estrogen metabolism in mammary carcinogenesis

Dual roles of estrogen metabolism in mammary carcinogenesis

ERβ in breast cancer—Onlooker, passive player, or active protector?

Overexpression of the Insulin-Like Growth Factor I Receptor and Activation of the AKT Pathway in Hyperplastic Endometrium

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