Role of receptor complexes in the extranuclear actions of estrogen receptor α in breast cancer

Song, Robert X.-D.; Fan, Ping; Yue, Wei; Chen, Yucai; Santen, Richard J.

doi:10.1677/erc.1.01322

Cited by 65 publications

(62 citation statements)

References 69 publications

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“…Activation of AKT and overexpression of EGF and ERBB receptors are consistent with previous observations in MCF7-LTED cells and related breast cancer conditions (Masamura et al, 1995;Jeng et al, 1998;Shim et al, 2000;McClelland et al, 2001;Knowlden et al, 2003;Osborne et al, 2005;Yue et al, 2005;Song et al, 2006;Beeram et al, 2007;LewisWambi et al, 2008;Santen et al, 2008;Ghayad et al, 2009). Notably, ERBB2 amplification was associated with resistance to endocrine therapies (Ellis et al, 2006), and treatment with the mTOR inhibitor RAD001 increased letrozole efficacy in a neoadjuvant setting of ERa-positive breast cancer (Baselga et al, 2009).…”

Section: Resultssupporting

confidence: 85%

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

et al. 2010

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Endocrine therapies targeting the proliferative effect of 17b-estradiol through estrogen receptor a (ERa) are the most effective systemic treatment of ERa-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The longterm estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERa. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were predicted to be influenced by transcription factors known to be involved in acquired resistance or cell proliferation (for example, interferon regulatory transcription factor 1 and E2F1, respectively) but, notably, not by canonical ERa transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)-to pS167-ERa were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERa-negative status, early response to letrozole and tamoxifen, and recurrence after tamoxifen treatment. In accordance with these profiles, MCF7-LTED cells showed increased sensitivity to inhibition of FGFR-mediated signaling with PD173074. This study provides mechanistic insight into acquired resistance to endocrine therapies of breast cancer and highlights a potential therapeutic strategy.

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Section: Resultssupporting

confidence: 85%

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

et al. 2010

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“…This suggests that AR might be recruited to membranes by other membrane proteins, thereby facilitating the flow of signals from AR to Akt and possibly to other signaling proteins. Consistent with this idea, ER␣ was found to be capable of activating signaling from the insulin-like growth factor-1 receptor by a mechanism involving direct binding of ER␣ to the insulinlike growth factor-1R (45). Post-translational modifications, such as phosphorylation (46) or palmitoylation (47), would be another mechanism by which AR might be recruited to membrane sites.…”

Section: Discussionmentioning

confidence: 84%

Phosphoinositide 3-Kinase-independent Non-genomic Signals Transit from the Androgen Receptor to Akt1 in Membrane Raft Microdomains

Cinar

Mukhopadhyay

Meng

et al. 2007

Journal of Biological Chemistry

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The serine-threonine kinase, Akt1/protein kinase B␣ is an important mediator of growth, survival, and metabolic signaling. Recent studies have implicated cholesterol-rich, lipid raft microdomains in survival signals mediated by Akt1. Here we address the role of lipid raft membranes as a potential site of intersection of androgenic and Akt1 signaling. A subpopulation of androgen receptor (AR) was found to localize to a lipid raft subcellular compartment in LNCaP prostate cancer cells. Endogenous AR interacted with endogenous Akt1 preferentially in lipid raft fractions and androgen substantially enhanced the interaction between the two proteins. The association of AR with Akt1 was inhibited by the anti-androgen, bicalutamide, but was not affected by inhibition of phosphoinositide 3-kinase (PI3K). Androgen promoted endogenous Akt1 activity in lipid raft fractions, in a PI3K-independent manner, within 10 min of treatment. Fusion of a lipid raft targeting sequence to AR enhanced localization of the receptor to rafts, and stimulated Akt1 activity in response to androgen, while reducing the cells' dependence on constitutive signaling through PI3K for cell survival. These findings suggest that signals channeled through AR and Akt1 intersect by a mechanism involving formation within lipid raft membranes of an androgen-responsive, extranuclear AR/Akt1 complex. Our results indicate that cholesterol-rich membrane microdomains play a role in transmitting nongenomic signals involving androgen and the Akt pathway in prostate cancer cells. Androgen receptor (AR),3 a member of the nuclear receptor superfamily of transcription factors, is an important regulator of reproductive physiology as a mediator of the biological activities of androgen (1). AR also plays a role in the pathogenesis of prostate cancer (PCa), including progression to the androgen-independent state and metastasis (2, 3). Upon androgen binding, the AR undergoes conformational changes and translocates from the cytosol to the nucleus (4), where the receptor-hormone complex regulates the expression of target genes (5).In addition to this well recognized genomic function, AR has been demonstrated to activate intracellular signaling pathways by a rapid (occurring in minutes) non-genomic process activated in response to hormonal stimulation (6, 7). The mechanisms underlying the non-canonical pathways involving the AR and other nuclear receptors are still poorly understood, however, possible nongenomic roles for the AR have been described (8 -12). For example, androgen promotes oocyte maturation, in both Xenopus (10) and mouse (12), by a transcription-independent mechanism that involves the classical AR (12,14). Another report showed that cells treated with 17␤-estradiol (E2) or androgen resulted in cell proliferation mediated by the rapid formation of a cytosolic signaling complex containing estrogen receptor-␣ or -␤ (ER␣ or ER␤ (depending on the cell type)), AR, and the non-receptor tyrosine kinase, Src (8). Similarly, Kousteni et al. (9) showed that ER␣, ER␤, or AR...

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“…2B, top panel) and in xenografts (data not shown) and were inhibited by the pure antiestrogen, fulvestrant. 8,11 We further demonstrated that activated MAP kinase is implicated in the enhanced growth of LTED cells since inhibitors of MAP kinase such as PD98059 or U-0126 block the incorporation of tritiated thymidine into DNA. 7 To demonstrate proof of the principle of MAP kinase participation, we stimulated activation of MAP kinase in wild type MCF-7 cells by administering TGFα (data not shown).…”

Section: Phenomenon Of Hypersensitivity: Mechanisms and Pathwaysmentioning

confidence: 87%

Adaptation to Estradiol Deprivation Causes Up-Regulation of Growth Factor Pathways and Hypersensitivity to Estradiol in Breast Cancer Cells

Santen

Song

Masamura

et al. 2008

Advances in Experimental Medicine and Biology

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Deprivation of estrogen causes breast tumors in women to adapt and develop enhanced sensitivity to this steroid. Accordingly, women relapsing after treatment with oophorectomy, which substantially lowers estradiol for a prolonged period, respond secondarily to aromatase inhibitors with tumor regression. We have utilized in vitro and in vivo model systems to examine the biologic processes whereby Long Term Estradiol Deprivation (LTED) causes cells to adapt and develop hypersensitivity to estradiol. Several mechanisms are associated with this response including upregulation of ERα and the MAP kinase, PI-3-kinase and mTOR growth factor pathways. ERα is 4-10 fold up-regulated as a result of demethylation of its C promoter, is nuclear receptor then co-opts a classical growth factor pathway using SHC, Grb-2 and Sos. is induces rapid nongenomic effects which are enhanced in LTED cells.The molecules involved in the nongenomic signaling process have been identified. Estradiol binds to cell membrane-associated ERα which physically associates with the adaptor protein SHC and induces its phosphorylation. In turn, SHC binds Grb-2 and Sos which results in the rapid activation of MAP kinase. These nongenomic effects of estradiol produce biologic effects as evidenced by Elk-1 activation and by morphologic changes in cell membranes. Additional effects include activation of the PI-3-kinase and mTOR pathways through estradiol-induced binding of ERα to the IGF-1 and EGF receptors.A major question is how ERα locates in the plasma membrane since it does not contain an inherent membrane localization signal. We have provided evidence that the IGF-1 receptor serves as an anchor for ERα in the plasma membrane. Estradiol causes phosphorylation of the adaptor protein, SHC and the IGF-1 receptor itself. SHC, after binding to ERα, serves as the "glue" which tethers ERα to SHC binding sites on the activated IFG-1 receptors. Use of siRNA methodology to knock down SHC allows the conclusion that SHC is needed for ERα to localize in the plasma membrane.In order to abrogate growth factor induced hypersensitivity, we have utilized a drug, farnesylthiosalicylic acid, which blocks the binding of GTP-Ras to its membrane acceptor protein, galectin 1 and reduces the activation of MAP kinase. We have shown that this drug is a potent inhibitor of mTOR and this provides the major means for inhibition of cell proliferation. The concept of "adaptive hypersensitivity" and the mechanisms responsible for this phenomenon have important clinical implications. The efficacy of aromatase inhibitors in patients relapsing on tamoxifen could be explained by this mechanism and inhibitors of growth factor pathways should reverse the hypersensitivity phenomenon and result in prolongation of the efficacy of hormonal therapy for breast cancer.

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Role of receptor complexes in the extranuclear actions of estrogen receptor α in breast cancer

Cited by 65 publications

References 69 publications

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

Phosphoinositide 3-Kinase-independent Non-genomic Signals Transit from the Androgen Receptor to Akt1 in Membrane Raft Microdomains

Adaptation to Estradiol Deprivation Causes Up-Regulation of Growth Factor Pathways and Hypersensitivity to Estradiol in Breast Cancer Cells

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