Kinase-Specific Phosphorylation of the Estrogen Receptor Changes Receptor Interactions with Ligand, Deoxyribonucleic Acid, and Coregulators Associated with Alterations in Estrogen and Tamoxifen Activity

Likhite, Varsha S.; Stossi, Fabio; Kim, Kyuri; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.

doi:10.1210/me.2006-0068

Cited by 160 publications

(145 citation statements)

References 58 publications

(80 reference statements)

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“…2B) (Paszek et al, 2005). Interestingly, force-generated activation of ERK may also influence cell proliferation, alter tissue behavior and drive anti-estrogen resistance during breast cancer treatment, through phosphorylation of ERα, recruitment of ERα co-activators or enhanced transcriptional activity, in a ligand-independent manner (Likhite, Stossi, Kim, Katzenellenbogen, & Katzenellenbogen, 2006). Indeed, tamoxifen, the anti-estrogen used in the treatment of breast cancer, has been shown to reduce breast density and therefore the risk of recurrences (Atkinson, Warren, Bingham, & Day, 1999).…”

Section: Associated Pathologiesmentioning

confidence: 99%

Mammary epithelial cell: Influence of extracellular matrix composition and organization during development and tumorigenesis

Kass

Erler

Dembo

et al. 2007

The International Journal of Biochemistry & Cell Biology

273

220

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Stromal-epithelial interactions regulate mammary gland development and are critical for the maintenance of tissue homeostasis. The extracellular matrix, which is a proteinaceous component of the stroma, regulates mammary epithelial growth, survival, migration and differentiation through a repertoire of transmembrane receptors, of which integrins are the best characterized. Integrins modulate cell fate by reciprocally transducing biochemical and biophysical cues between the cell and the extracellular matrix, facilitating processes such as embryonic branching morphogenesis and lactation in the mammary gland. During breast development and cancer progression, the extracellular matrix is dynamically altered such that its composition, turnover, processing and orientation change dramatically. These modifications influence mammary epithelial cell shape, and modulate growth factor and hormonal responses to regulate processes including branching morphogenesis and alveolar differentiation. Malignant transformation of the breast is also associated with significant matrix remodeling and a progressive stiffening of the stroma that can enhance mammary epithelial cell growth, perturb breast tissue organization, and promote cell invasion and survival. In this review, we discuss the role of stromal-epithelial interactions in normal and malignant mammary epithelial cell behavior. We specifically focus on how dynamic modulation of the biochemical and biophysical properties of the extracellular matrix elicit a dialogue with the mammary epithelium through transmembrane integrin receptors to influence tissue morphogenesis, homeostasis and malignant transformation. Keywords NIH Public AccessAuthor Manuscript Int J Biochem Cell Biol. Author manuscript; available in PMC 2009 March 19. Published in final edited form as:Int J Biochem Cell Biol. 2007 ; 39(11): 1987-1994. doi:10.1016/j.biocel.2007.025. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptCell facts• Stromal-epithelial interactions regulate mammary epithelial cell growth and differentiation during embryonic and postnatal development.• The spatial organization and composition of the extracellular matrix influence mammary epithelial cell behavior.• Alterations in extracellular matrix receptor expression can enable malignant transformation of the mammary epithelial cells.• Differences in the biophysical properties of the extracellular matrix due to an increase in deposit and/or cross-linking can induce the malignant transformation of mammary epithelial cells.

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Section: Associated Pathologiesmentioning

confidence: 99%

Mammary epithelial cell: Influence of extracellular matrix composition and organization during development and tumorigenesis

Kass

Erler

Dembo

et al. 2007

The International Journal of Biochemistry & Cell Biology

273

220

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“…In breast cancer cells phosphorylation of the Ser-118 residue in the human ERa A/B domain by growth factors stimulated mitogen-activated protein kinase (Kato et al, 1995;Bunone et al, 1996;Chen et al, 2000;Medunjanin et al, 2005;Park et al, 2005;Weitsman et al, 2006) results in the potentiation of the ER ligandindependent transcriptional activation function (AF-1). Interestingly, it has been proposed that phosphorylation in Ser-118 may be associated with an increase in estrogen agonism, progression of breast cancer, resistance to tamoxifen therapy and estrogen-independent growth of MCF-7 cells (Likhite et al, 2006;Murphy et al, 2006). Recently, it has been shown that the pure ER antagonist ICI 182,780 (ICI) can also induce ER phosphorylation in Ser-118 (Lipfert et al, 2006;De los Santos et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Activation of the unliganded estrogen receptor by prolactin in breast cancer cells

et al. 2009

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Both prolactin (PRL) and estrogen (E2) are involved in the pathogenesis and progression of mammary neoplasia, but the mechanisms by which these hormones interact to exert their effects in breast cancer cells are not well understood. We show here that PRL is able to activate the unliganded estrogen receptor (ER). In breast cancer cells, PRL activates a reporter plasmid containing estrogen response elements (EREs) and induces the ER target gene pS2. These actions are blocked by the antagonist ICI 182,780, showing that ER is required for the PRLmediated effect. Moreover, PRL leads to phosphorylation of ERa in serine-118 (P-ERa), a modification related to the potentiation of ligand-independent transcriptional activation. In addition, PRL mimics the effect of E2 on target gene expression by inducing cyclical recruitment of ERa and P-ERa to ERE-containing promoters, resulting in recruitment of co-activators and acetylation of histone H3. Finally, PRL induces expression of c-Myc and Cyclin D1 and leads to increased cell proliferation, which is specifically antagonized by ICI 182,780 or ERa depletion. These results show that ligand-independent ERa activation appears to be an important component of the proliferative and transcriptional actions of PRL in breast cancer cells.

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“…Phosphorylation of ERa-Ser118 by ERK increases binding of coactivator SRC-3 (Likhite et al 2006) and renders ERa hypersensitive to E 2 (Vendrell et al 2005). Phosphorylation of ERa-Ser118 decreases ERa affinity for TAM and reduces binding to DNA, when ERa is TAM-bound (Likhite et al 2006). In a TAM-resistant cell line obtained by selection after prolonged exposure to TAM, ERK activity was found to be elevated and pERa-Ser118 was increased (Vendrell et al 2005).…”

Section: Discussionmentioning

confidence: 97%

“…Ser-118 is perhaps the best-studied site of ERa phosphorylation and is widely considered to be a target of ERK, although other kinases such as the glycogen synthase kinse-3 (GSK-3), inhibitor of kappa B kinase (IKK) a, cyclin-dependent kinase 7 (CDK7) and mammalian target of rapamycin (mTOR)/ ribosomal protein S6 kinase (p70S6K) may also phosphorylate this site (de Leeuw et al 2011). Phosphorylation of ERa-Ser118 by ERK increases binding of coactivator SRC-3 (Likhite et al 2006) and renders ERa hypersensitive to E 2 (Vendrell et al 2005). Phosphorylation of ERa-Ser118 decreases ERa affinity for TAM and reduces binding to DNA, when ERa is TAM-bound (Likhite et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Results of previous studies have indicated that phosphorylation of ERa by serine/threonine protein kinases induces TAM resistance (Kato et al 1995, Campbell et al 2001, Park et al 2005, Yamashita et al 2005, Likhite et al 2006, Yamnik et al 2009, Guo et al 2010, de Leeuw et al 2011. Ser-118 and Ser-167 are two of the most reported phosphorylation sites of ERa.…”

Section: Il6 Phosphorylates Era At Ser118 and Ser167 In Ovca Cells Bymentioning

confidence: 99%

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IL6 induces TAM resistance via kinase-specific phosphorylation of ERα in OVCA cells

Wang

Niu

Guo

et al. 2015

Journal of Molecular Endocrinology

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About 40-60% of ovarian cancer (OVCA) cases express ERa, but only a small proportion of patients respond clinically to anti-estrogen treatment with estrogen receptor (ER) antagonist tamoxifen (TAM). The mechanism of TAM resistance in the course of OVCA progression remains unclear. However, IL6 plays a critical role in the development and progression of OVCA. Our recent results indicated that IL6 secreted by OVCA cells may promote the resistance of these cells to TAM via ER isoforms and steroid hormone receptor coactivator-1. Here we demonstrate that both exogenous (a relatively short period of treatment with recombinant IL6) and endogenous IL6 (generated as a result of transfection with a plasmid encoding sense IL6) increases expression of pERa-Ser118 and pERa-Ser167 in non-IL6-expressing A2780 cells, while deleting endogenous IL6 expression in IL6-overexpressing CAOV-3 cells (by transfection with a plasmid encoding antisense IL6) reduces expression of pERa-Ser118 and pERa-Ser167, indicating that IL6-induced TAM resistance may also be associated with increased expression of pERa-Ser118 and pERa-Ser167 in OVCA cells. Results of further investigation indicate that IL6 phosphorylates ERa at Ser118 and Ser167 by triggering activation of MEK/ERK and phosphotidylinositol 3 kinase/Akt signaling, respectively, to activate the ER pathway and thereby induce OVCA cells resistance to TAM. These results indicate that IL6 secreted by OVCA cells may also contribute to the refractoriness of these cells to TAM via the crosstalk between ER and IL6-mediated intracellular signal transduction cascades. Overexpression of IL6 not only plays an important role in OVCA progression but also promotes TAM resistance. Our results indicate that TAM-IL6-targeted adjunctive therapy may lead to a more effective intervention than TAM alone.Key Words

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Kinase-Specific Phosphorylation of the Estrogen Receptor Changes Receptor Interactions with Ligand, Deoxyribonucleic Acid, and Coregulators Associated with Alterations in Estrogen and Tamoxifen Activity

Cited by 160 publications

References 58 publications

Mammary epithelial cell: Influence of extracellular matrix composition and organization during development and tumorigenesis

Mammary epithelial cell: Influence of extracellular matrix composition and organization during development and tumorigenesis

Activation of the unliganded estrogen receptor by prolactin in breast cancer cells

IL6 induces TAM resistance via kinase-specific phosphorylation of ERα in OVCA cells

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