The Role of Growth Factor Receptor Pathways in Human Breast Cancer Cells Adapted to Long-term Estrogen Deprivation

Sabnis, Gauri; Jelovac, Danijela; Long, Brian J.; Brodie, Angela

doi:10.1158/0008-5472.can-04-4092

Cited by 103 publications

(110 citation statements)

References 26 publications

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“…As supported by the molecular data presented above, acquired resistance may be mediated by constitutive activation of ERa and growth factor signaling pathway cross-talk (Martin et al, 2003;Jelovac et al, 2005;Sabnis et al, 2005;Santen et al, 2005;Masri et al, 2008). Thus, the identities of genes differentially expressed during MCF7-LTED adaptation may support the important role of the non-genomic function of ERa.…”

Section: Resultsmentioning

confidence: 83%

“…Current literature supports the hypothesis that acquired resistance is mainly mediated by molecular events that-particularly in the case of resistance to AIs-lead to constitutive activation of ERa and growth factor signaling pathway cross-talk (Clarke et al, 2003;Martin et al, 2003;Yue et al, 2003;Jelovac et al, 2005;Normanno et al, 2005;Sabnis et al, 2005;Santen et al, 2005;Masri et al, 2008). On the basis of these studies, several clinical trials have attempted to overcome resistance through combination with growth factor signaling inhibitors Massarweh and Schiff, 2006).…”

Section: Introductionmentioning

confidence: 84%

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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: Resultsmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 84%

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

et al. 2010

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“…To address this question, studies have been undertaken to investigate longterm estrogen deprivation (LTED), since AIs function to effectively block the synthesis of estrogens. LTED cells have been generated in Dr. R. Santen's, Dr. M. Dowsett's, Dr. R. Nicholson's and Dr. A. Brodie's laboratories [31][32][33][34]. The key findings from these laboratories have been reviewed in a recent report [35].…”

Section: Acquired Resistancementioning

confidence: 99%

“…The estrogen withdrawal cell lines are not exactly equivalent to AI resistant cell lines, as demonstrated through the comparison of molecular features between the estrogen withdrawal cell lines and letrozole resistant cell line generated in Brodie's laboratory [33,36,37]. As discussed above, exemestane, letrozole and anastrozole inhibit aromatase through different mechanisms.…”

Section: Bmentioning

confidence: 99%

New experimental models for aromatase inhibitor resistance

Chen

Masri

Hong

et al. 2007

The Journal of Steroid Biochemistry and Molecular Biology

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Clinical trials have demonstrated the importance of aromatase inhibitor (AI) therapy in the effective treatment of hormone-dependent breast cancers. In contrast to tamoxifen, an antagonist of the estrogen receptor (ER), AIs have shown to be better tolerated along with decreased recurrence rates of the disease. Currently, three third-generation AIs are being used: exemestane, letrozole and anastrozole. Our laboratory is attempting to understand several aspects of aromatase inhibitor functionality. In this paper, we first review recent findings from our structure-function studies of aromatase as well as the molecular characterization of the interaction between AIs and aromatase. Based on these studies, we propose new evidence for the interaction of letrozole and exemestane with aromatase. In addition, we will discuss recent results generated from our AI-resistant cell lines. Our laboratory has generated MCF-7aro cells that are resistant to letrozole, anastrozole, exemestane and tamoxifen. Basic functional characterization of aromatase and ERα in these resistant cell lines has been done and microarray analysis has been employed in order to better understand the mechanism responsible for AI resistance on a genome-wide scale. The results generated so far suggest the presence of at least four types of resistant cell lines. Overall, the information presented in this paper supplements our understanding of AI function, and such information can be valuable for the development of treatment strategies against AI resistant breast cancers.

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“…Mammary epithelial cell growth and differentiation is influenced by the changing roles of factors such as steroid and peptide hormones, growth factors, and cytokines (Nicholson et al 1999, Sabnis et al 2005. Activin is a member of the transforming growth factor b (TGF-b) superfamily of growth factors and regulates mammary gland development, differentiation during lactation, and becomes deregulated as breast cancer increases in pathological grade (Reis et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Activin and estrogen crosstalk regulates transcription in human breast cancer cells

Burdette

Woodruff²

2007

Endocr Relat Cancer

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Activin is a member of the transforming growth factor b superfamily that regulates mammary cell function during development, lactation, and in cancer. Activin slows the growth of breast cancer cells by inducing G 0 /G 1 cell cycle arrest. Estrogen is a steroid hormone that stimulates the proliferation of mammary epithelial cells in development and oncogenesis. The crosstalk between estrogen and activin that regulates activin ligand expression, activin and estrogen signal transduction, and cell cycle arrest was investigated in this study. Estrogen antagonized activindependent production of plasminogen activator inhibitor 1 (PAI-1) mRNA, while activin repressed estrogen-dependent transcription of trefoil factor 1. The repression of estrogen signaling by activin was recapitulated using a simple estrogen response element-luciferase construct and was enhanced in the presence of overexpressed estrogen receptor a (ERa). In contrast, estrogenmediated repression of activin signaling could not be recapitulated on a simple CAGA Smadbinding element but did inhibit the short PAI-1 promoter, p3TP-luciferase, especially when ERa was overexpressed. Repression of both estrogen-and activin-regulated transcription was found to be ligand induced and Smad3 dependent. In addition to transcriptional repression, estrogen also reduced the amount of activin B mRNA and protein produced by MCF7 breast cancer cells. These studies demonstrate the importance of activin and estrogen crosstalk during mammary cell growth and cancer initiation.

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The Role of Growth Factor Receptor Pathways in Human Breast Cancer Cells Adapted to Long-term Estrogen Deprivation

Cited by 103 publications

References 26 publications

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

New experimental models for aromatase inhibitor resistance

Activin and estrogen crosstalk regulates transcription in human breast cancer cells

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