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Title: A new method for stranded whole transcriptome RNA-seq.
Creator: Rhodes, Lyndsay, Miller, David F.B., Yan, Pearlly S., Buechlein, Aaron, Rodriguez, Benjamin A., Yilmaz, Ayse, Goel, Shokhi, Collins-Burow, Bridgette M., Braun, Chris, Pradeep,...
Show moreRhodes, Lyndsay, Miller, David F.B., Yan, Pearlly S., Buechlein, Aaron, Rodriguez, Benjamin A., Yilmaz, Ayse, Goel, Shokhi, Collins-Burow, Bridgette M., Braun, Chris, Pradeep, Sunila, Rupaimoole, Rajesha, Dalkilic, Mehmet, Sood, Anil K., Burow, Matthew E., Tang, Haixu, Huang, Tim H., Liu, Yunlong, Rusch, Douglas B., Nephew, Kenneth P.
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Abstract / Description: This report describes an improved protocol to generate stranded, barcoded RNA-seq libraries to capture the whole transcriptome. By optimizing the use of duplex specific nuclease (DSN) to remove ribosomal RNA reads from stranded barcoded libraries, we demonstrate improved efficiency of multiplexed next generation sequencing (NGS). This approach detects expression profiles of all RNA types, including miRNA (microRNA), piRNA (Piwi-interacting RNA), snoRNA (small nucleolar RNA), lincRNA (long non...
Show moreThis report describes an improved protocol to generate stranded, barcoded RNA-seq libraries to capture the whole transcriptome. By optimizing the use of duplex specific nuclease (DSN) to remove ribosomal RNA reads from stranded barcoded libraries, we demonstrate improved efficiency of multiplexed next generation sequencing (NGS). This approach detects expression profiles of all RNA types, including miRNA (microRNA), piRNA (Piwi-interacting RNA), snoRNA (small nucleolar RNA), lincRNA (long non-coding RNA), mtRNA (mitochondrial RNA) and mRNA (messenger RNA) without the use of gel electrophoresis. The improved protocol generates high quality data that can be used to identify differential expression in known and novel coding and non-coding transcripts, splice variants, mitochondrial genes and SNPs (single nucleotide polymorphisms).
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Date Issued: 2013-04-01
Identifier: fgcu_ir_000441
Format: Citation

Title: Adult human mesenchymal stem cells enhance breast tumorigenesis and promote hormone independence.
Creator: Rhodes, Lyndsay, Muir, Shannon E., Elliott, Steven, Guillot, Lori M., Antoon, James W., Penfornis, Patrice, Tilghman, Syreeta L., Salvo, Virgilo A., Fonseca, Juan P., Lacey,...
Show moreRhodes, Lyndsay, Muir, Shannon E., Elliott, Steven, Guillot, Lori M., Antoon, James W., Penfornis, Patrice, Tilghman, Syreeta L., Salvo, Virgilo A., Fonseca, Juan P., Lacey, Michelle R., Beckman, Barbara S., McLachlan, John A., Rowan, Brian G., Pochampally, Radhika, Burow, Matthew E.
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Abstract / Description: Adult human mesenchymal stem cells (hMSCs) have been shown to home to sites of breast cancer and integrate into the tumor stroma. We demonstrate here the effect of hMSCs on primary breast tumor growth and the progression of these tumors to hormone independence. Co-injection of bone marrow-derived hMSCs enhances primary tumor growth of the estrogen receptor-positive, hormone-dependent breast carcinoma cell line MCF-7 in the presence or absence of estrogen in SCID/beige mice. We also show...
Show moreAdult human mesenchymal stem cells (hMSCs) have been shown to home to sites of breast cancer and integrate into the tumor stroma. We demonstrate here the effect of hMSCs on primary breast tumor growth and the progression of these tumors to hormone independence. Co-injection of bone marrow-derived hMSCs enhances primary tumor growth of the estrogen receptor-positive, hormone-dependent breast carcinoma cell line MCF-7 in the presence or absence of estrogen in SCID/beige mice. We also show hormone-independent growth of MCF-7 cells when co-injected with hMSCs. These effects were found in conjunction with increased immunohistochemical staining of the progesterone receptor in the MCF-7/hMSC tumors as compared to MCF-7 control tumors. This increase in PgR expression indicates a link between MCF-7 cells and MSCs through ER-mediated signaling. Taken together, our data reveal the relationship between tumor microenvironment and tumor growth and the progression to hormone independence. This tumor stroma-cell interaction may provide a novel target for the treatment of estrogen receptor-positive, hormone-independent, and endocrine-resistant breast carcinoma.
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Date Issued: 2009-07-12
Identifier: fgcu_ir_000457
Format: Citation

Title: AKT Regulation of Estrogen Receptor B Transcriptional Activity in Breast Cancer.
Creator: Rhodes, Lyndsay, Duong, Bich N., Elliott, Steven, Frigo, Daniel E., Melnik, Lilia I., Tomchuck, Suzanne, Lebeau, Helena P., David, Odile, Beckman, Barbara S., Alam, Jawed,...
Show moreRhodes, Lyndsay, Duong, Bich N., Elliott, Steven, Frigo, Daniel E., Melnik, Lilia I., Tomchuck, Suzanne, Lebeau, Helena P., David, Odile, Beckman, Barbara S., Alam, Jawed, Bratton, Melyssa R., McLachlan, John A., Burow, Matthew E., author
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Abstract / Description: Growth factor activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway has been shown to activate the estrogen receptor (ER) α and to mediate tamoxifen resistance in breast cancer. Here, we investigated the regulation of the transcriptional activity of the newer ERβ by PI3K-AKT signaling. Tissue arrays of breast cancer specimens showed a positive association between the expressions of AKT and ERβ in the clinical setting. Reporter gene assays using pharmacologic and molecular...
Show moreGrowth factor activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway has been shown to activate the estrogen receptor (ER) α and to mediate tamoxifen resistance in breast cancer. Here, we investigated the regulation of the transcriptional activity of the newer ERβ by PI3K-AKT signaling. Tissue arrays of breast cancer specimens showed a positive association between the expressions of AKT and ERβ in the clinical setting. Reporter gene assays using pharmacologic and molecular inhibitors of AKT and constitutively active AKT revealed for the first time the ability of AKT to (a) potentiate ERβ activity and (b) target predominantly the activation function-2 (AF2) domain of the receptor, with a requirement for residue K269. Given the importance of coactivators in ER transcriptional activity, we further investigated the possible involvement of steroid receptor coactivator 1 (SRC1) and glucocorticoid receptor-interacting protein 1 (GRIP1) in AKT regulation of ERβ. Mammalian two-hybrid assays revealed that AKT enhanced both SRC1 and GRIP1 recruitment to the ERβ-AF2 domain, and reporter gene analyses revealed that AKT and GRIP1 cooperatively potentiated ERβ-mediated transcription to a level much greater than either factor alone. Investigations into AKT regulation of GRIP with mammalian one-hybrid assays showed that AKT potentiated the activation domains of GRIP1 itself, and in vitro kinase assays revealed that AKT directly phosphorylated GRIP1. The cross-talk between the PI3K-AKT and ERβ pathways, as revealed by the ability of AKT to regulate several components of ERβ-mediated transcription, may represent an important aspect that may influence breast cancer response to endocrine therapy.
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Date Issued: 2006-09-01
Identifier: fgcu_ir_000461
Format: Citation

Title: Altered Death Receptor Signaling Promotes Epithelial-to-Mesenchymal Transition and Acquired Chemoresistance.
Creator: Rhodes, Lyndsay, Antoon, James W., Lai, Rongye, Struckhoff, Amanda P., Nitzchke, Ashley M., Elliott, Steven, Martin, Elizabeth C., Yoon, Nam Seung, Salvo, Virgilo A., Shan, Bin,...
Show moreRhodes, Lyndsay, Antoon, James W., Lai, Rongye, Struckhoff, Amanda P., Nitzchke, Ashley M., Elliott, Steven, Martin, Elizabeth C., Yoon, Nam Seung, Salvo, Virgilo A., Shan, Bin, Beckman, Barbara S., Nephew, Kenneth P., Burow, Matthew E.
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Abstract / Description: Altered death receptor signaling and resistance to subsequent apoptosis is an important clinical resistance mechanism. Here, we investigated the role of death receptor resistance in breast cancer progression. Resistance of the estrogen receptor alpha (ER)-positive, chemosensitive MCF7 breast cancer cell line to tumor necrosis factor (TNF) was associated with loss of ER expression and a multi-drug resistant phenotype. Changes in three major pathways were involved in this transition to a...
Show moreAltered death receptor signaling and resistance to subsequent apoptosis is an important clinical resistance mechanism. Here, we investigated the role of death receptor resistance in breast cancer progression. Resistance of the estrogen receptor alpha (ER)-positive, chemosensitive MCF7 breast cancer cell line to tumor necrosis factor (TNF) was associated with loss of ER expression and a multi-drug resistant phenotype. Changes in three major pathways were involved in this transition to a multidrug resistance phenotype: ER, Death Receptor and epithelial to mesenchymal transition (EMT). Resistant cells exhibited altered ER signaling, resulting in decreased ER target gene expression. The death receptor pathway was significantly altered, blocking extrinsic apoptosis and increasing NF-kappaB survival signaling. TNF resistance promoted EMT changes, resulting in a more aggressive phenotype. This first report identifying specific mechanisms underlying acquired resistance to TNF could lead to a better understanding of the progression of breast cancer in response to chemotherapy treatment.
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Date Issued: 2012-07-27
Identifier: fgcu_ir_000444
Format: Document (PDF)

Title: Antiestrogenic Effects of the Novel Sphingosine Kinase-2 Inhibitor ABC294640.
Creator: Rhodes, Lyndsay, Antoon, James W., White, Martin D., Meacham, William D., Slaughter, Evelyn M., Muir, Shannon E., Elliott, Steven, Ashe, Hasina B., Wiese, Thomas E., Smith,...
Show moreRhodes, Lyndsay, Antoon, James W., White, Martin D., Meacham, William D., Slaughter, Evelyn M., Muir, Shannon E., Elliott, Steven, Ashe, Hasina B., Wiese, Thomas E., Smith, Charles D., Burow, Matthew E., Beckman, Barbara S.
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Abstract / Description: Alterations in sphingolipid metabolism have been shown to contribute to the development of endocrine resistance and breast cancer tumor survival. Sphingosine kinase (SK), in particular, is overexpressed in breast cancer and is a promising target for breast cancer drug development. In this study, we used the novel SK inhibitor ABC294640 as a tool to explore the relationship between SK and estrogen (E2) receptor (ER) signaling in breast cancer cells. Treatment with ABC294640 decreased E2...
Show moreAlterations in sphingolipid metabolism have been shown to contribute to the development of endocrine resistance and breast cancer tumor survival. Sphingosine kinase (SK), in particular, is overexpressed in breast cancer and is a promising target for breast cancer drug development. In this study, we used the novel SK inhibitor ABC294640 as a tool to explore the relationship between SK and estrogen (E2) receptor (ER) signaling in breast cancer cells. Treatment with ABC294640 decreased E2-stimulated ERE-luciferase activity in both MCF-7 and ER-transfected HEK293 cells. Furthermore, the inhibitor reduced E2-mediated transcription of the ER-regulated genes progesterone receptor and SDF-1. Competitive receptor-binding assays revealed that ABC294640 binds in the antagonist ligand-binding domain of the ER, acting as a partial antagonist similar to tamoxifen. Finally, treatment with ABC294640 inhibited ER-positive breast cancer tumor formation in vivo. After 15 d of treatment with ABC294640, tumor volume was reduced by 68.4% (P < 0.05; n = 5) compared with control tumors, with no marked weight loss or illness. Taken together, these results provide strong evidence that this novel SK inhibitor, which had not previously been known to interact with E2 signaling pathways, has therapeutic potential in treating ER-positive breast cancer via inhibition of both SK and ER signaling.
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Date Issued: 2010-11-01
Identifier: fgcu_ir_000454
Format: Citation

Title: Argonaute 2 Expression Correlates with a Luminal B Breast Cancer Subtype and Induces Estrogen Receptor Alpha Isoform Variation.
Creator: Rhodes, Lyndsay, Conger, Adrienne K., Martin, Elizabeth C., Yan, Thomas J., Hoang, Van T., La, Jacqueline, Anbalagan, Muralidharan, Burks, Hope E., Rowan, Brian G., Nephew,...
Show moreRhodes, Lyndsay, Conger, Adrienne K., Martin, Elizabeth C., Yan, Thomas J., Hoang, Van T., La, Jacqueline, Anbalagan, Muralidharan, Burks, Hope E., Rowan, Brian G., Nephew, Kenneth P., Collins-Burow, Bridgette M., Burow, Matthew E.
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Abstract / Description: Estrogen receptor alpha (ERα) signaling pathways are frequently disrupted in breast cancer and contribute to disease progression. ERα signaling is multifaceted and many ERα regulators have been identified including transcription factors and growth factor pathways. More recently, microRNAs (miRNAs) are shown to deregulate ERα activity in breast carcinomas, with alterations in both ERα and miRNA expression correlating to cancer progression. In this study, we show that a high expression of...
Show moreEstrogen receptor alpha (ERα) signaling pathways are frequently disrupted in breast cancer and contribute to disease progression. ERα signaling is multifaceted and many ERα regulators have been identified including transcription factors and growth factor pathways. More recently, microRNAs (miRNAs) are shown to deregulate ERα activity in breast carcinomas, with alterations in both ERα and miRNA expression correlating to cancer progression. In this study, we show that a high expression of Argonaute 2 (AGO2), a translation regulatory protein and mediator of miRNA function, correlates with the luminal B breast cancer subtype. We further demonstrate that a high expression of AGO2 in ERα+ tumors correlates with a poor clinical outcome. MCF-7 breast cancer cells overexpressing AGO2 (MCF7-AGO2) altered ERα downstream signaling and selective ERα variant expression. Enhanced ERα-36, a 36 kDa ERα isoform, protein and gene expression was observed in vitro. Through quantitative polymerase chain reaction (qPCR), we demonstrate decreased basal expression of the full-length ERα and progesterone receptor genes, in addition to loss of estrogen stimulated gene expression in vitro. Despite the loss, MCF-7-AGO2 cells demonstrated increased estrogen stimulated tumorigenesis in vivo. Together with our clinical findings on AGO2 expression and the luminal B subtype, we suggest that AGO2 is a regulator of altered ERα signaling in breast tumors.
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Date Issued: 2016-09-01
Identifier: fgcu_ir_000431
Format: Document (PDF)

Title: Dual regulation by microRNA-200b-3p and microRNA-200b-5p in the inhibition of epithelial-to-mesenchymal transition in triple-negative breast cancer.
Creator: Rhodes, Lyndsay, Martin, Elizabeth C., Segar, Chris H., Miller, David F.B., Buechlein, Aaron, Nephew, Kenneth P., Burow, Matthew E., Collins-Burow, Bridgette M.
Abstract / Description: Epithelial to mesenchymal transition (EMT) involves loss of an epithelial phenotype and activation of a mesenchymal one. Enhanced expression of genes associated with a mesenchymal transition includes ZEB1/2, TWIST, and FOXC1. miRNAs are known regulators of gene expression and altered miRNA expression is known to enhance EMT in breast cancer. Here we demonstrate that the tumor suppressive miRNA family, miR-200, is not expressed in triple negative breast cancer (TNBC) cell lines and that miR...
Show moreEpithelial to mesenchymal transition (EMT) involves loss of an epithelial phenotype and activation of a mesenchymal one. Enhanced expression of genes associated with a mesenchymal transition includes ZEB1/2, TWIST, and FOXC1. miRNAs are known regulators of gene expression and altered miRNA expression is known to enhance EMT in breast cancer. Here we demonstrate that the tumor suppressive miRNA family, miR-200, is not expressed in triple negative breast cancer (TNBC) cell lines and that miR-200b-3p over-expression represses EMT, which is evident through decreased migration and increased CDH1 expression. Despite the loss of migratory capacity following re-expression of miR-200b-3p, no subsequent loss of the conventional miR-200 family targets and EMT markers ZEB1/2 was observed. Next generation RNA-sequencing analysis showed that enhanced expression of pri-miR-200b lead to ectopic expression of both miR-200b-3p and miR-200b-5p with multiple isomiRs expressed for each of these miRNAs. Furthermore, miR-200b-5p was expressed in the receptor positive, epithelial breast cancer cell lines but not in the TNBC (mesenchymal) cell lines. In addition, a compensatory mechanism for miR-200b-3p/200b-5p targeting, where both miRNAs target the RHOGDI pathway leading to non-canonical repression of EMT, was demonstrated. Collectively, these data are the first to demonstrate dual targeting by miR-200b-3p and miR-200b-5p and a previously undescribed role for microRNA processing and strand expression in EMT and TNBC, the most aggressive breast cancer subtype.
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Date Issued: 2015-01-01
Identifier: fgcu_ir_000432
Format: Document (PDF)

Title: Dynamic regulation of ROCK in tumor cells controls CXCR4-driven adhesion events.
Creator: Rhodes, Lyndsay, Vitko, Jason R., Rana, Manish K., Davis, Carter T., Foderingham, Kamau E., Liu, Chi-Hsin, Elliott, Steven, Zhu, Yun, Burow, Matthew E., Worthylake, Rebecca A.
Abstract / Description: CXCR4 is a chemokine receptor often found aberrantly expressed on metastatic tumor cells. To investigate CXCR4 signaling in tumor cell adhesion, we stably overexpressed CXCR4 in MCF7 breast tumor cells. Cell attachment assays demonstrate that stimulation of the receptor with its ligand, CXCL12, promotes adhesion of MCF7-CXCR4 cells to both extracellular matrix and endothelial ligands. To more closely mimic the conditions experienced by a circulating tumor cell, we performed the attachment...
Show moreCXCR4 is a chemokine receptor often found aberrantly expressed on metastatic tumor cells. To investigate CXCR4 signaling in tumor cell adhesion, we stably overexpressed CXCR4 in MCF7 breast tumor cells. Cell attachment assays demonstrate that stimulation of the receptor with its ligand, CXCL12, promotes adhesion of MCF7-CXCR4 cells to both extracellular matrix and endothelial ligands. To more closely mimic the conditions experienced by a circulating tumor cell, we performed the attachment assays under shear stress conditions. We found that CXCL12-induced tumor cell attachment is much more pronounced under flow. ROCK is a serine/threonine kinase associated with adhesion and metastasis, which is regulated by CXCR4 signaling. Thus, we investigated the contribution of ROCK activity during CXC12-induced adhesion events. Our results demonstrate a biphasic regulation of ROCK in response to adhesion. During the initial attachment, inhibition of ROCK activity is required. Subsequently, re-activation of ROCK activity is required for maturation of adhesion complexes and enhanced tumor cell migration. Interestingly, CXCL12 partially reduces the level of ROCK activity generated by attachment, which supports a model in which stimulation with CXCL12 regulates tumor cell adhesion events by providing an optimal level of ROCK activity for effective migration.
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Date Issued: 2010-02-03
Identifier: fgcu_ir_000458
Format: Citation

Title: Effects of 7-O Substitutions on Estrogenic and Anti-Estrogenic Activities of Daidzein Analogues in MCF-7 Breast Cancer Cells.
Creator: Rhodes, Lyndsay, Jiang, Quan, Payton-Stewart, Florastina, Elliott, Steven, Elliott, Steven, Zhang, Qiang, Zheng, Shilong, Bhatnagar, Deepak, Boue, Stephen M., Collins-Burow,...
Show moreRhodes, Lyndsay, Jiang, Quan, Payton-Stewart, Florastina, Elliott, Steven, Elliott, Steven, Zhang, Qiang, Zheng, Shilong, Bhatnagar, Deepak, Boue, Stephen M., Collins-Burow, Bridgette M., Sridhar, Jayalakshmi, Stevens, Cheryl, McLachlan, John A., Wiese, Thomas E., Burow, Matthew E., Wang, Guangdi
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Abstract / Description: Daidzein (1) is a natural estrogenic isoflavone. We report here that 1 can be transformed into anti-estrogenic ligands by simple alkyl substitutions of the 7-hydroxyl hydrogen. To test the effect of such structural modifications on the hormonal activities of the resulting compounds, a series of daidzein analogues have been designed and synthesized. When MCF-7 cells were treated with the analogues, those resulting from hydrogen substitution by isopropyl (3d), isobutyl (3f), cyclopentyl (3g),...
Show moreDaidzein (1) is a natural estrogenic isoflavone. We report here that 1 can be transformed into anti-estrogenic ligands by simple alkyl substitutions of the 7-hydroxyl hydrogen. To test the effect of such structural modifications on the hormonal activities of the resulting compounds, a series of daidzein analogues have been designed and synthesized. When MCF-7 cells were treated with the analogues, those resulting from hydrogen substitution by isopropyl (3d), isobutyl (3f), cyclopentyl (3g), and pyrano- (2) inhibited cell proliferation, estrogen-induced transcriptional activity, and estrogen receptor (ER) regulated progesterone receptor (PgR) gene expression. However, methyl (3a) and ethyl (3b) substitutions of the hydroxyl proton only led to moderate reduction of the estrogenic activities. These results demonstrated the structural requirements for the transformation of daidzein from an ER agonist to an antagonist. The most effective analogue, 2, was found to reduce in vivo estrogen stimulated MCF-7 cell tumorigenesis using a xenograft mouse model.
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Date Issued: 2010-07-29
Identifier: fgcu_ir_000455
Format: Citation

Title: Effects of human mesenchymal stem cells on ER-positive human breast carcinoma cells mediated through ER-SDF-1/CXCR4 crosstalk.
Creator: Rhodes, Lyndsay, Antoon, James W., Muir, Shannon E., Elliott, Steven, Beckman, Barbara S., Burow, Matthew E.
Abstract / Description: Adult human mesenchymal stem cells (hMSC) have been shown to home to sites of carcinoma and affect biological processes, including tumour growth and metastasis. Previous findings have been conflicting and a clear understanding of the effects of hMSCs on cancer remains to be established. Therefore, we set out to investigate the impact of hMSCs on the oestrogen receptor positive, hormone-dependent breast carcinoma cell line MCF-7.
Date Issued: 2010-11-18
Identifier: fgcu_ir_000453
Format: Document (PDF)

Title: Effects of SDF-1–CXCR4 signaling on microRNA expression and tumorigenesis in estrogen receptor-alpha (ER-α)-positive breast cancer cells.
Creator: Rhodes, Lyndsay, Bratton, Melyssa R., Zhu, Yun, Tilghman, Syreeta L., Muir, Shannon E., Salvo, Virgilo A., Tate, Chandra R., Elliott, Steven, Nephew, Kenneth P., Burow, Matthew...
Show moreRhodes, Lyndsay, Bratton, Melyssa R., Zhu, Yun, Tilghman, Syreeta L., Muir, Shannon E., Salvo, Virgilo A., Tate, Chandra R., Elliott, Steven, Nephew, Kenneth P., Burow, Matthew E., Collins-Burow, Bridgette M.
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Abstract / Description: The majority of breast cancer cases ultimately become unresponsive to endocrine therapies, and this progression of breast cancer from hormone-responsive to hormone-independent represents an area in need of further research. Additionally, hormone-independent carcinomas are characterized as being more aggressive and metastatic, key features of more advanced disease. Having previously shown the ability of the stromal-cell derived factor-1 (SDF-1)–CXCR4 signaling axis to promote primary...
Show moreThe majority of breast cancer cases ultimately become unresponsive to endocrine therapies, and this progression of breast cancer from hormone-responsive to hormone-independent represents an area in need of further research. Additionally, hormone-independent carcinomas are characterized as being more aggressive and metastatic, key features of more advanced disease. Having previously shown the ability of the stromal-cell derived factor-1 (SDF-1)–CXCR4 signaling axis to promote primary tumorigenesis and hormone independence by overexpressing CXCR4 in MCF-7 cells, in this study we further examined the role of SDF-1/CXCR4 in the endogenously CXCR4-positive, estrogen receptor α (ER-α)-positive breast carcinoma cell line, MDA–MB-361. In addition to regulating estrogen-induced and hormone-independent tumor growth, CXCR4 signaling stimulated the epithelial-to-mesenchymal transition, evidenced by decreased CDH1 expression following SDF-1 treatment. Furthermore, inhibition of CXCR4 with the small molecule inhibitor AMD3100 induced CDH1 gene expression and inhibited CDH2 gene expression in MDA–MB-361 cells. Further, exogenous SDF-1 treatment induced ER-α-phosphorylation in both MDA–MB-361 and MCF-7–CXCR4 cells, demonstrating ligand-independent activation of ER-α through CXCR4 crosstalk. qPCR microRNA array analyses of the MDA–MB-361 and MCF-7–CXCR4 cell lines revealed changes in microRNA expression profiles induced by SDF-1, consistent with a more advanced disease phenotype and further supporting our hypothesis that the SDF-1/CXCR4 signaling axis drives ER-α-positive breast cancer cells to a hormone independent and more aggressive phenotype. In this first demonstration of SDF-1–CXCR4-induced microRNAs in breast cancer, we suggest that this signaling axis may promote tumorigenesis via microRNA regulation. These findings represent future potential therapeutic targets for the treatment of hormone-independent and endocrine-resistant breast cancer.
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Date Issued: 2011-11-01
Identifier: fgcu_ir_000451
Format: Citation

Title: Elevated expression of long intergenic non-coding RNA HOTAIR in a basal-like variant of MCF-7 breast cancer cells.
Creator: Rhodes, Lyndsay, Zhuang, Yan, Nguyen, Hong T., Burow, Matthew E., El‐Dahr, Samir S., Yao, Xiao, Cao, Subing, Flemington, Erik K., Nephew, Kenneth P., Fang, Fang, Collins-Burow,...
Show moreRhodes, Lyndsay, Zhuang, Yan, Nguyen, Hong T., Burow, Matthew E., El‐Dahr, Samir S., Yao, Xiao, Cao, Subing, Flemington, Erik K., Nephew, Kenneth P., Fang, Fang, Collins-Burow, Bridgette M., Yu, Qiang, Jayawickramarajah, Janarthanan, Shan, Bin
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Abstract / Description: Epigenetic regulation of gene expression is critical to phenotypic maintenance and transition of human breast cancer cells. HOX antisense intergenic RNA (HOTAIR) is a long intergenic non‐coding RNA that epigenetically represses gene expression via recruitment of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase. Elevated expression of HOTAIR promotes progression of breast cancer. In the current study we examined the expression and function of HOTAIR in MCF‐7‐TNR cells, a...
Show moreEpigenetic regulation of gene expression is critical to phenotypic maintenance and transition of human breast cancer cells. HOX antisense intergenic RNA (HOTAIR) is a long intergenic non‐coding RNA that epigenetically represses gene expression via recruitment of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase. Elevated expression of HOTAIR promotes progression of breast cancer. In the current study we examined the expression and function of HOTAIR in MCF‐7‐TNR cells, a derivative of the luminal‐like breast cancer cell line MCF‐7 that acquired resistance to TNF‐α‐induced cell death. The expression of HOTAIR, markers of the luminal‐like and basal‐like subtypes, and growth were compared between MCF‐7 and MCF‐7‐TNR cells. These variables were further assessed upon inhibition of HOTAIR, EZH2, p38 MAPK, and SRC kinase in MCF‐7‐TNR cells. When compared with MCF‐7 cells, MCF‐7‐TNR cells exhibited an increase in the expression of HOTAIR, which correlated with characteristics of a luminal‐like to basal‐like transition as evidenced by dysregulated gene expression and accelerated growth. MCF‐7‐TNR cells exhibited reduced suppressive histone H3 lysine27 trimethylation on the HOTAIR promoter. Inhibition of HOTAIR and EZH2 attenuated the luminal‐like to basal‐like transition in terms of gene expression and growth in MCF‐7‐TNR cells. Inhibition of p38 and SRC diminished HOTAIR expression and the basal‐like phenotype in MCF‐7‐TNR cells. HOTAIR was robustly expressed in the native basal‐like breast cancer cells and inhibition of HOTAIR reduced the basal‐like gene expression and growth. Our findings suggest HOTAIR‐mediated regulation of gene expression and growth associated with the basal‐like phenotype of breast cancer cells.
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Date Issued: 2015-01-01
Identifier: fgcu_ir_000435
Format: Citation

Title: Endocrine Disruptor Regulation of MicroRNA Expression in Breast Carcinoma Cells.
Creator: Rhodes, Lyndsay, Tilghman, Syreeta L., Bratton, Melyssa R., Segar, H. Chris, Martin, Elizabeth C., Li, Meng, McLachlan, John A., Wiese, Thomas E., Nephew, Kenneth P., Burow,...
Show moreRhodes, Lyndsay, Tilghman, Syreeta L., Bratton, Melyssa R., Segar, H. Chris, Martin, Elizabeth C., Li, Meng, McLachlan, John A., Wiese, Thomas E., Nephew, Kenneth P., Burow, Matthew E.
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Abstract / Description: Several environmental agents termed “endocrine disrupting compounds” or EDCs have been reported to bind and activate the estrogen receptor-α (ER). The EDCs DDT and BPA are ubiquitously present in the environment, and DDT and BPA levels in human blood and adipose tissue are detectable in most if not all women and men. ER-mediated biological responses can be regulated at numerous levels, including expression of coding RNAs (mRNAs) and more recently non-coding RNAs (ncRNAs). Of the ncRNAs,...
Show moreSeveral environmental agents termed “endocrine disrupting compounds” or EDCs have been reported to bind and activate the estrogen receptor-α (ER). The EDCs DDT and BPA are ubiquitously present in the environment, and DDT and BPA levels in human blood and adipose tissue are detectable in most if not all women and men. ER-mediated biological responses can be regulated at numerous levels, including expression of coding RNAs (mRNAs) and more recently non-coding RNAs (ncRNAs). Of the ncRNAs, microRNAs have emerged as a target of estrogen signaling. Given the important implications of EDC-regulated ER function, we sought to define the effects of BPA and DDT on microRNA regulation and expression levels in estrogen-responsive human breast cancer cells.
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Date Issued: 2012-03-05
Identifier: fgcu_ir_000448
Format: Document (PDF)

Title: Glyceollin I, a Novel Antiestrogenic Phytoalexin Isolated from Activated Soy.
Creator: Rhodes, Lyndsay, Zimmermann, M. Carla, Tilghman, Syreeta L., Boue, Stephen M., Salvo, Virgilo A., Elliott, Steven, Skripnikova, Elena V., Ashe, Hasina B., Payton-Stewart,...
Show moreRhodes, Lyndsay, Zimmermann, M. Carla, Tilghman, Syreeta L., Boue, Stephen M., Salvo, Virgilo A., Elliott, Steven, Skripnikova, Elena V., Ashe, Hasina B., Payton-Stewart, Florastina, Fonseca, Juan P., Corbitt, Cynthia, Collins-Burow, Bridgette M., Howell, Melanie H., Lacey, Michelle, Shih, Betty Y., Carter-Wientjes, Carol, Cleveland, Thomas E., McLachlan, John A., Burow, Matthew E.
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Abstract / Description: Glyceollins, a group of novel phytoalexins isolated from activated soy, have recently been demonstrated to be novel antiestrogens that bind to the estrogen receptor (ER) and inhibit estrogen-induced tumor progression. Our previous publications have focused specifically on inhibition of tumor formation and growth by the glyceollin mixture, which contains three glyceollin isomers (I, II, and III). Here, we show the glyceollin mixture is also effective as a potential antiestrogenic, therapeutic...
Show moreGlyceollins, a group of novel phytoalexins isolated from activated soy, have recently been demonstrated to be novel antiestrogens that bind to the estrogen receptor (ER) and inhibit estrogen-induced tumor progression. Our previous publications have focused specifically on inhibition of tumor formation and growth by the glyceollin mixture, which contains three glyceollin isomers (I, II, and III). Here, we show the glyceollin mixture is also effective as a potential antiestrogenic, therapeutic agent that prevents estrogen-stimulated tumorigenesis and displays a differential pattern of gene expression from tamoxifen. By isolating the individual glyceollin isomers (I, II, and III), we have identified the active antiestrogenic component by using competition binding assays with human ERalpha and in an estrogen-responsive element-based luciferase reporter assay. We identified glyceollin I as the active component of the combined glyceollin mixture. Ligand-receptor modeling (docking) of glyceollin I, II, and III within the ERalpha ligand binding cavity demonstrates a unique type II antiestrogenic confirmation adopted by glyceollin I but not isomers II and III. We further compared the effects of glyceollin I to the antiestrogens, 4-hydroxytamoxifen and ICI 182,780 (fulvestrant), in MCF-7 breast cancer cells and BG-1 ovarian cancer cells on 17beta-estradiol-stimulated expression of progesterone receptor and stromal derived factor-1alpha. Our results establish a novel inhibition of ER-mediated gene expression and cell proliferation/survival. Glyceollin I may represent an important component of a phytoalexin-enriched food (activated) diet in terms of chemoprevention as well as a novel therapeutic agent for hormone-dependent tumors.
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Date Issued: 2010-01-01
Identifier: fgcu_ir_000459
Format: Citation

Title: Glyceollin, a novel regulator of mTOR/p70S6 in estrogen receptor positive breast cancer.
Creator: Rhodes, Lyndsay, Bratton, Melyssa R., Martin, Elizabeth C., Elliott, Steven, Collins-Burow, Bridgette M., McLachlan, John A., Wiese, Thomas E., Boue, Stephen M., Burow, Matthew E.
Abstract / Description: An estimated 70% of breast cancer tumors utilize estrogen receptor (ER) signaling to maintain tumorigenesis and targeting of the estrogen receptor is a common method of treatment for these tumor types. However, ER-positive (+) breast cancers often acquire drug resistant or altered ER activity in response to anti-estrogens. Here we demonstrate glyceollin, an activated soy compound, has anti-estrogen effects in breast cancers. We demonstrate through estrogen response element luciferase and...
Show moreAn estimated 70% of breast cancer tumors utilize estrogen receptor (ER) signaling to maintain tumorigenesis and targeting of the estrogen receptor is a common method of treatment for these tumor types. However, ER-positive (+) breast cancers often acquire drug resistant or altered ER activity in response to anti-estrogens. Here we demonstrate glyceollin, an activated soy compound, has anti-estrogen effects in breast cancers. We demonstrate through estrogen response element luciferase and phosphorylation-ER mutants that the effects of glyceollin arise from mechanisms distinct from conventional endocrine therapies. We show that glyceollin suppresses estrogen response element activity; however, it does not affect ER-alpha (α) phosphorylation levels. Additionally we show that glyceollin suppresses the phosphorylation of proteins known to crosstalk with ER signaling, specifically we demonstrate an inhibition of ribosomal protein S6 kinase, 70 kDa (p70S6) phosphorylation following glyceollin treatment. Our data suggests a mechanism for glyceollin inhibition of ERα through the induced suppression of p70S6 and demonstrates novel mechanisms for ER inhibition.
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Date Issued: 2015-06-01
Identifier: fgcu_ir_000434
Format: Citation

Title: Glyceollin-Elicited Soy Protein Consumption Induces Distinct Transcriptional Effects As Compared to Standard Soy Protein.
Creator: Rhodes, Lyndsay, Wood, Charles E., Boue, Stephen M., Collins-Burow, Bridgette M., Register, Thomas C., Cline, J. Mark, Dewi, Fitriya N., Burow, Matthew E.
Abstract / Description: Glyceollins are stress-induced compounds in soybeans with bioactive properties distinct from parent soy isoflavones. The goals of this study were to evaluate the effects of dietary glyceollin-enriched and standard soy protein isolates and identify candidate target pathways of glyceollins on transcriptional profiles within mammary gland tissue. Thirty female postmenopausal cynomolgus monkeys were randomized to diets containing one of three protein sources for 3 weeks: (1) control casein...
Show moreGlyceollins are stress-induced compounds in soybeans with bioactive properties distinct from parent soy isoflavones. The goals of this study were to evaluate the effects of dietary glyceollin-enriched and standard soy protein isolates and identify candidate target pathways of glyceollins on transcriptional profiles within mammary gland tissue. Thirty female postmenopausal cynomolgus monkeys were randomized to diets containing one of three protein sources for 3 weeks: (1) control casein/lactalbumin (C/L), (2) standard soy protein containing 194 mg/day isoflavones (SOY), and (3) glyceollin-enriched soy protein containing 189 mg/day isoflavones + 134 mg/day glyceollins (GLY). All diets contained a physiologic dose of estradiol (E2) (1 mg/day). All doses are expressed in human equivalents scaled by caloric intake. Relative to the control C/L diet, the GLY diet resulted in greater numbers of differentially regulated genes, which showed minimal overlap with those of SOY. Effects of GLY related primarily to pathways involved in lipid and carbohydrate metabolism, including peroxisome proliferator-activated receptor (PPAR)-γ and AMP-activated protein kinase (AMPK) signaling, adipocytokine expression, triglyceride synthesis, and lipase activity. Notable genes upregulated by the GLY diet included PPAR-γ, adiponectin, leptin, lipin 1, and lipoprotein lipase. The GLY diet also resulted in lower serum total cholesterol, specifically nonhigh-density lipoprotein cholesterol, and increased serum triglycerides as compared to the C/L diet. No effects of GLY or SOY were seen on serum insulin, adipocytokines, or vascular and bone turnover markers. These preliminary findings suggest that glyceollin-enriched soy protein has divergent effects from standard soy with some specificity for adipocyte activity and nutrient metabolism.
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Date Issued: 2011-11-29
Identifier: fgcu_ir_000449
Format: Citation

Title: Glyceollins as novel targeted therapeutic for the treatment of triple-negative breast cancer.
Creator: Rhodes, Lyndsay, Tilghman, Syreeta L., Boue, Stephen M., Wang, Shuchun, Khalili, Hafez, Muir, Shannon E., Bratton, Melyssa R., Zhang, Qiang, Wang, Guandi, Burow, Matthew E.,...
Show moreRhodes, Lyndsay, Tilghman, Syreeta L., Boue, Stephen M., Wang, Shuchun, Khalili, Hafez, Muir, Shannon E., Bratton, Melyssa R., Zhang, Qiang, Wang, Guandi, Burow, Matthew E., Collins-Burow, Bridgette M.
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Abstract / Description: The purpose of this study was to investigate the effects of glyceollins on the suppression of tumorigenesis in triple‑negative breast carcinoma cell lines. We further explored the effects of glyceollins on microRNA and protein expression in MDA‑MB‑231 cells. Triple‑negative (ER‑, PgR‑ and Her2/neu‑) breast carcinoma cells were used to test the effects of glyceollins on tumorigenesis in vivo. Following this procedure, unbiased microarray analysis of microRNA expression was performed....
Show moreThe purpose of this study was to investigate the effects of glyceollins on the suppression of tumorigenesis in triple‑negative breast carcinoma cell lines. We further explored the effects of glyceollins on microRNA and protein expression in MDA‑MB‑231 cells. Triple‑negative (ER‑, PgR‑ and Her2/neu‑) breast carcinoma cells were used to test the effects of glyceollins on tumorigenesis in vivo. Following this procedure, unbiased microarray analysis of microRNA expression was performed. Additionally, we examined the changes in the proteome induced by glyceollins in the MDA‑MB‑231 cells. Tumorigenesis studies revealed a modest suppression of MDA‑MB‑231 and MDA‑MB‑468 cell tumor growth in vivo. In response to glyceollins we observed a distinct change in microRNA expression profiles and proteomes of the triple‑negative breast carcinoma cell line, MDA‑MB‑231. Our results demonstrated that the glyceollins, previously described as anti‑estrogenic agents, also exert antitumor activity in triple‑negative breast carcinoma cell systems. This activity correlates with the glyceollin alteration of microRNA and proteomic expression profiles.
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Date Issued: 2011-09-21
Identifier: fgcu_ir_000445
Format: Citation

Title: Human mesenchymal stem cells as mediators of breast carcinoma tumorigenesis and progression.
Creator: Rhodes, Lyndsay, Burow, Matthew E.
Abstract / Description: Breast cancer continues to be the most frequently diagnosed carcinoma in women in the U.S. [1,2] with one in eight (12%) women having the chance of developing some form of breast carcinoma over the course of their lifetime [3,4]. A tumor mass is composed of malignant cancer cells and nonmalignant benign cells. The benign cells include tumor endothelial cells, inflammatory cells, and stromal cells, as well as the extracellular matrix (ECM) that provides structural support to the malignant...
Show moreBreast cancer continues to be the most frequently diagnosed carcinoma in women in the U.S. [1,2] with one in eight (12%) women having the chance of developing some form of breast carcinoma over the course of their lifetime [3,4]. A tumor mass is composed of malignant cancer cells and nonmalignant benign cells. The benign cells include tumor endothelial cells, inflammatory cells, and stromal cells, as well as the extracellular matrix (ECM) that provides structural support to the malignant cells [5]. The tumor microenvironment has been shown to play an active part in tumorigenesis and cancer progression through structural support as well as secreted factors [6]. It is now understood that stromal fibroblasts within the tumor microenvironment can influence tumor cell activities, such as proliferation, survival, metastasis, and even tumor initiation
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Date Issued: 2010-01-01
Identifier: fgcu_ir_000456
Format: Citation

Title: Human Uterine Smooth Muscle and Leiomyoma Cells Differ in Their Rapid 17β-Estradiol Signaling: Implications for Proliferation.
Creator: Rhodes, Lyndsay, Nierth-Simpson, Erica N., Martin, Melvenia M., Chiang, Tung-Chin, Melnik, Lilia I., Muir, Shannon E., Burow, Matthew E., McLachlan, John A.
Abstract / Description: Uterine leiomyomas, benign uterine smooth muscle tumors that affect 30% of reproductive-aged women, are a significant health concern. The initiation event for these tumors is unclear, but 17β-estradiol (E2) is an established promoter of leiomyoma growth. E2 not only alters transcription of E2-regulated genes but also can rapidly activate signaling pathways. The aim of our study is to investigate the role of rapid E2-activated cytoplasmic signaling events in the promotion of leiomyomas....
Show moreUterine leiomyomas, benign uterine smooth muscle tumors that affect 30% of reproductive-aged women, are a significant health concern. The initiation event for these tumors is unclear, but 17β-estradiol (E2) is an established promoter of leiomyoma growth. E2 not only alters transcription of E2-regulated genes but also can rapidly activate signaling pathways. The aim of our study is to investigate the role of rapid E2-activated cytoplasmic signaling events in the promotion of leiomyomas. Western blot analysis revealed that E2 rapidly increases levels of phosphorylated protein kinase Cα (PKCα) in both immortalized uterine smooth muscle (UtSM) and leiomyoma (UtLM) cell lines, but increases levels of phosphorylated ERK1/2 only in UtLM cells. Our studies demonstrate a paradoxical effect of molecular and pharmacological inhibition of PKCα on ERK1/2 activation and cellular proliferation in UtLM and UtSM cells. PKCα inhibition decreases levels of phosphorylated ERK1/2 and proliferation in UtLM cells but raises these levels in UtSM cells. cAMP-PKA signaling is rapidly activated only in UtSM cells with E2 and inhibits ERK1/2 activation and proliferation. We therefore propose a model whereby E2’s rapid activation of PKCα and cAMP-PKA signaling plays a central role in the maintenance of a low proliferative index in normal uterine smooth muscle via its inhibition of the MAPK cascade and these pathways are altered in leiomyomas to promote MAPK activation and proliferation. These studies demonstrate that rapid E2-signaling pathways contribute to the promotion of leiomyomas.
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Date Issued: 2009-05-01
Identifier: fgcu_ir_000460
Format: Citation

Title: Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition.
Creator: Rhodes, Lyndsay, Antoon, James W., Nitzchke, Ashley M., Martin, Elizabeth C., Nam, Seungyoon, Wadsworth, Scott, Salvo, Virgilo A., Elliott, Steven, Collins-Burow, Bridgette M.,...
Show moreRhodes, Lyndsay, Antoon, James W., Nitzchke, Ashley M., Martin, Elizabeth C., Nam, Seungyoon, Wadsworth, Scott, Salvo, Virgilo A., Elliott, Steven, Collins-Burow, Bridgette M., Burow, Matthew E.
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Abstract / Description: Acquired chemoresistance and epithelial-to-mesenchymal transition (EMT) are hallmarks of cancer progression and of increasing clinical relevance. We investigated the role of miRNA and p38 mitogen-activated protein kinase (MAPK) signaling in the progression of breast cancer to a drug-resistant and mesenchymal phenotype. We demonstrate that acquired death receptor resistance results in increased hormone-independent tumorigenesis compared to hormone-sensitive parental cells. Utilizing global...
Show moreAcquired chemoresistance and epithelial-to-mesenchymal transition (EMT) are hallmarks of cancer progression and of increasing clinical relevance. We investigated the role of miRNA and p38 mitogen-activated protein kinase (MAPK) signaling in the progression of breast cancer to a drug-resistant and mesenchymal phenotype. We demonstrate that acquired death receptor resistance results in increased hormone-independent tumorigenesis compared to hormone-sensitive parental cells. Utilizing global miRNA gene expression profiling, we identified miRNA alterations associated with the development of death receptor resistance and EMT progression. We further investigated the role of p38 MAPK in this process, showing dose-dependent inactivation of p38 by its inhibitor RWJ67657 and decreased downstream ATF and NF‑κB signaling. Pharmacological inhibition of p38 also decreased chemoresistant cancer tumor growth in xenograft animal models. Interestingly, inhibition of p38 partially reversed the EMT changes found in this cell system, as illustrated by decreased gene expression of the EMT markers Twist, Snail, Slug and ZEB and protein and mRNA levels of Twist, a known EMT promoter, concomitant with decreased N‑cadherin protein. RWJ67657 treatment also altered the expression of several miRNAs known to promote therapeutic resistance, including miR‑200, miR‑303, miR‑302, miR‑199 and miR‑328. Taken together, our results demonstrate the roles of multiple microRNAs and p38 signaling in the progression of cancer and demonstrate the therapeutic potential of targeting the p38 MAPK pathway for reversing EMT in an advanced tumor phenotype.
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Date Issued: 2012-09-01
Identifier: fgcu_ir_000442
Format: Citation

Breast--Cancer. (23)	+ -
Estrogen--Receptors. (5)	+ -
CXCR4 (2)	+ -
Mesenchymal stem cells. (2)	+ -
Metastasis. (2)	+ -

Tumor Microenvironment (2)	+ -
mTOR (2)	+ -
AMD3100 (1)	+ -
Anti-estrogen (1)	+ -
Breast Cancer Cell (1)	+ -
Breast carcinoma (1)	+ -
Breast carcinoma (1)	+ -
CDH1 (1)	+ -
CXCL12 (1)	+ -
CXCR4 Signalling (1)	+ -
Conditioned Medium (1)	+ -
Duplex-specific nuclease (1)	+ -
E-cadherin (1)	+ -
EZH2 (1)	+ -
Endocrine Therapy Resistance (1)	+ -
Endocrine therapy (1)	+ -
Epithelial-to-mesenchymal transition (1)	+ -
Fulvestrant (1)	+ -
Gene expression. (1)	+ -
Glyceollin (1)	+ -
HDAC inhibitor (1)	+ -
HOTAIR (1)	+ -
Histone Deacetylase Inhibitors. (1)	+ -
Hormone independence (1)	+ -
Human Breast Adenocarcinoma Cell Line (1)	+ -

English (31)	+ -
eng (31)	+ -

Rhodes, Lyndsay (31)	+ -
Collins-Burow, Bridgette M. (20)	+ -
Elliott, Steven (18)	+ -
Martin, Elizabeth C. (13)	+ -
Nephew, Kenneth P. (11)	+ -

Antoon, James W. (7)	+ -
Beckman, Barbara S. (7)	+ -
Bratton, Melyssa R. (7)	+ -
McLachlan, John A. (7)	+ -
Muir, Shannon E. (6)	+ -
Salvo, Virgilo A. (6)	+ -
Tilghman, Syreeta L. (6)	+ -
Boue, Stephen M. (5)	+ -
Nitzchke, Ashley M. (4)	+ -
Tate, Chandra R. (4)	+ -
Wiese, Thomas E. (4)	+ -
Zhu, Yun (4)	+ -
Buechlein, Aaron (3)	+ -
Burks, Hope E. (3)	+ -
Flemington, Erik K. (3)	+ -
Hoang, Van T. (3)	+ -
Rowan, Brian G. (3)	+ -
Segar, Chris H. (3)	+ -
Shan, Bin (3)	+ -
Wang, Guandi (3)	+ -
Zhang, Qiang (3)	+ -
Anbalagan, Muralidharan (2)	+ -
Ashe, Hasina B. (2)	+ -
Bunnell, Bruce A. (2)	+ -

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