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G Protein-coupled Estrogen Receptor 1 (GPER1) and Insulin-like Growth Factor Binding Protein 1 (IGFBP-1) Are Key Components of Tamoxifen Action and the Development of Tamoxifen Resistance in Breast Cancer Cells.

Record Type:	Electronic resources : Monograph/item
Title/Author:	G Protein-coupled Estrogen Receptor 1 (GPER1) and Insulin-like Growth Factor Binding Protein 1 (IGFBP-1) Are Key Components of Tamoxifen Action and the Development of Tamoxifen Resistance in Breast Cancer Cells./
Author:	Zheng, Yan.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
Description:	133 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-12, Section: B.
Contained By:	Dissertations Abstracts International80-12B.
Subject:	Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13811186
ISBN:	9781392222447

G Protein-coupled Estrogen Receptor 1 (GPER1) and Insulin-like Growth Factor Binding Protein 1 (IGFBP-1) Are Key Components of Tamoxifen Action and the Development of Tamoxifen Resistance in Breast Cancer Cells.
Zheng, Yan.

G Protein-coupled Estrogen Receptor 1 (GPER1) and Insulin-like Growth Factor Binding Protein 1 (IGFBP-1) Are Key Components of Tamoxifen Action and the Development of Tamoxifen Resistance in Breast Cancer Cells. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 133 p.

Source: Dissertations Abstracts International, Volume: 80-12, Section: B.

Thesis (Ph.D.)--New Mexico State University, 2019.

This item must not be sold to any third party vendors.

G protein-coupled estrogen receptor 1 (GPER1) is a seven-transmembrane receptor that mediates rapid cell signaling events stimulated by estrogens. While the role that GPER1 has in the modulation of E2-responsive tissues and cancers is well documented, the molecular mechanisms that regulate GPER1 expression are currently not well defined. The recently identified GPER1-dependent mechanism of tamoxifen action in breast cancer cells underscores the importance of identifying mechanisms that regulate GPER1 expression in this cell type. We hypothesized that GPER1 expression in breast cancer cells is sensitive to [D-glucose] and provide data showing increased GPER1 expression when cells were cultured in low [D-glucose]. To determine if the observed accumulation of GPER1 was AMPK-dependent, small molecule stimulation or inhibition of AMPK was performed. AMPK inhibition decreased GPER1 accumulation in cells grown in low [D-glucose] while the AMPK-activating compound AICAR increased GPER1 accumulation in cells grown in high [D-glucose] media. Additionally, transfection of cells with a plasmid expressing constitutively active AMPK resulted in increased GPER1 accumulation. To determine if [D-glucose]-dependent GPER1 accumulation altered breast cancer cell response to tamoxifen, cells grown in the presence of decreasing [D-glucose] were co-treated with tamoxifen and IGFBP-1 transcription was measured. The results from these experiments reveal that D-glucose deprivation increased tamoxifen-induced IGFBP-1 transcription suggesting that [D-glucose] modulates breast cancer cell sensitivity to tamoxifen treatment. Taken together, these results identify a previously unknown mechanism that regulates GPER1 expression that alters the sensitivity of breast cancer cells to tamoxifen.Since we had identified that IGFBP-1 was the target gene of GPER1 in our previous work, and we had shown that the treatment of tamoxifen induced the accumulation of IGFBP-1 in a GPER1-dependent manner, we wanted to further investigate the impact of the accumulation of IGFBP-1 in a longer term on tamoxifen-sensitive breast cancer cells. IGFBP-1 is one of the components of insulin-like growth factor (IGF) system. IGF system plays a significantly role in cellular processes, including proliferation, survival, and mitogenesis. The IGF system consists of two soluble ligands, IGF-1 and IGF-2; two transmembrane receptors, IGF-1R and IGF-2R; and six high affinity IGF binding proteins, IGFBPs 1-6. Evidence shows that the IGF system is involved in breast cancer. For example, at least 50% of breast cancer tumors have elevated IGF-1R signaling; the level of circulating IGF-1 is found positively associated with the incident of estrogen receptor positive breast cancer. Tamoxifen, a selective estrogen receptor modulator and antagonist for estrogen receptor alpha (ERα) in breast tissue, is a commonly prescribed adjuvant treatment for patients presenting with ERα-positive breast cancer. However, tamoxifen resistance also occurs, and its exact mechanism is not well understood. Recently, we discovered that the accumulation of IGFBP-1 was stimulated by tamoxifen treatment, which subsequently prevented the activation of IGF-1R and inhibited the proliferation in MCF-7 cells. As a result, we hypothesized that the accumulation of IGFBP-1 due to the long-term tamoxifen exposure would result in tamoxifen resistance. In order to mimic the accumulation of IGFBP-1 after tamoxifen treatment, we employed MCF-7 and T-47D breast cancer cells to generate stable cell lines with IGFBP-1 overexpression. We found that the expression of IGF-1R was largely reduced in both MCF7-BP1 and T47D-BP1 cells, which was also observed in tamoxifen resistant MCF-7 and T-47D cells. Furthermore, we demonstrated that both MCF7-BP1 and T47D-BP1 were not responsive to tamoxifen, and epidermal growth factor receptor (EGFR) signaling pathway was significantly upregulated, as shown by higher levels of EGFR, phospho-EGFR (pEGFR), and phospho-Erk (pErk). Also, we found that the inhibition of Erk phosphorylation by MEK1 inhibitor PD98059 sensitized the stable cells to tamoxifen, showing that elevated pErk was protective against tamoxifen. Lastly, the transient knockdown of IGFBP-1 in MCF7-BP1 and T47D-BP1 resulted in significantly lower level of pErk and increased sensitivity to tamoxifen, further showing the role of IGFBP1 accumulation in the establishment of tamoxifen resistance and the activation of EGFR/MAPK pathway.Taken together, the work in this dissertation revealed that AMPK pathway regulated the expression of GPER1 in ER α positive breast cancer cells. The upregulation of GPER1 was shown to be correlated to the tamoxifen efficacy in terms of IGFBP-1 expression. In conclusion, this work provided the insight observation of GPER1 regulation, IGFBP-1 function, and the novel route of tamoxifen resistance establishment. (Abstract shortened by ProQuest).

ISBN: 9781392222447Subjects--Topical Terms:

518028
Biochemistry.

G Protein-coupled Estrogen Receptor 1 (GPER1) and Insulin-like Growth Factor Binding Protein 1 (IGFBP-1) Are Key Components of Tamoxifen Action and the Development of Tamoxifen Resistance in Breast Cancer Cells.
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520 $a G protein-coupled estrogen receptor 1 (GPER1) is a seven-transmembrane receptor that mediates rapid cell signaling events stimulated by estrogens. While the role that GPER1 has in the modulation of E2-responsive tissues and cancers is well documented, the molecular mechanisms that regulate GPER1 expression are currently not well defined. The recently identified GPER1-dependent mechanism of tamoxifen action in breast cancer cells underscores the importance of identifying mechanisms that regulate GPER1 expression in this cell type. We hypothesized that GPER1 expression in breast cancer cells is sensitive to [D-glucose] and provide data showing increased GPER1 expression when cells were cultured in low [D-glucose]. To determine if the observed accumulation of GPER1 was AMPK-dependent, small molecule stimulation or inhibition of AMPK was performed. AMPK inhibition decreased GPER1 accumulation in cells grown in low [D-glucose] while the AMPK-activating compound AICAR increased GPER1 accumulation in cells grown in high [D-glucose] media. Additionally, transfection of cells with a plasmid expressing constitutively active AMPK resulted in increased GPER1 accumulation. To determine if [D-glucose]-dependent GPER1 accumulation altered breast cancer cell response to tamoxifen, cells grown in the presence of decreasing [D-glucose] were co-treated with tamoxifen and IGFBP-1 transcription was measured. The results from these experiments reveal that D-glucose deprivation increased tamoxifen-induced IGFBP-1 transcription suggesting that [D-glucose] modulates breast cancer cell sensitivity to tamoxifen treatment. Taken together, these results identify a previously unknown mechanism that regulates GPER1 expression that alters the sensitivity of breast cancer cells to tamoxifen.Since we had identified that IGFBP-1 was the target gene of GPER1 in our previous work, and we had shown that the treatment of tamoxifen induced the accumulation of IGFBP-1 in a GPER1-dependent manner, we wanted to further investigate the impact of the accumulation of IGFBP-1 in a longer term on tamoxifen-sensitive breast cancer cells. IGFBP-1 is one of the components of insulin-like growth factor (IGF) system. IGF system plays a significantly role in cellular processes, including proliferation, survival, and mitogenesis. The IGF system consists of two soluble ligands, IGF-1 and IGF-2; two transmembrane receptors, IGF-1R and IGF-2R; and six high affinity IGF binding proteins, IGFBPs 1-6. Evidence shows that the IGF system is involved in breast cancer. For example, at least 50% of breast cancer tumors have elevated IGF-1R signaling; the level of circulating IGF-1 is found positively associated with the incident of estrogen receptor positive breast cancer. Tamoxifen, a selective estrogen receptor modulator and antagonist for estrogen receptor alpha (ERα) in breast tissue, is a commonly prescribed adjuvant treatment for patients presenting with ERα-positive breast cancer. However, tamoxifen resistance also occurs, and its exact mechanism is not well understood. Recently, we discovered that the accumulation of IGFBP-1 was stimulated by tamoxifen treatment, which subsequently prevented the activation of IGF-1R and inhibited the proliferation in MCF-7 cells. As a result, we hypothesized that the accumulation of IGFBP-1 due to the long-term tamoxifen exposure would result in tamoxifen resistance. In order to mimic the accumulation of IGFBP-1 after tamoxifen treatment, we employed MCF-7 and T-47D breast cancer cells to generate stable cell lines with IGFBP-1 overexpression. We found that the expression of IGF-1R was largely reduced in both MCF7-BP1 and T47D-BP1 cells, which was also observed in tamoxifen resistant MCF-7 and T-47D cells. Furthermore, we demonstrated that both MCF7-BP1 and T47D-BP1 were not responsive to tamoxifen, and epidermal growth factor receptor (EGFR) signaling pathway was significantly upregulated, as shown by higher levels of EGFR, phospho-EGFR (pEGFR), and phospho-Erk (pErk). Also, we found that the inhibition of Erk phosphorylation by MEK1 inhibitor PD98059 sensitized the stable cells to tamoxifen, showing that elevated pErk was protective against tamoxifen. Lastly, the transient knockdown of IGFBP-1 in MCF7-BP1 and T47D-BP1 resulted in significantly lower level of pErk and increased sensitivity to tamoxifen, further showing the role of IGFBP1 accumulation in the establishment of tamoxifen resistance and the activation of EGFR/MAPK pathway.Taken together, the work in this dissertation revealed that AMPK pathway regulated the expression of GPER1 in ER α positive breast cancer cells. The upregulation of GPER1 was shown to be correlated to the tamoxifen efficacy in terms of IGFBP-1 expression. In conclusion, this work provided the insight observation of GPER1 regulation, IGFBP-1 function, and the novel route of tamoxifen resistance establishment. (Abstract shortened by ProQuest).
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