Genetically engineered ERα-positive breast cancer mouse models

Dabydeen, Sarah A.; Furth, Priscilla A.

doi:10.1530/erc-13-0512

Cited by 33 publications

(28 citation statements)

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“…Mouse models of ERα + breast cancer are limited, and few develop distant metastases [31, 32]. Although patient-derived xenografts are proving useful in elucidating the behavior of some breast cancer subtypes in vivo, they require highly immunocompromised hosts [67, 68], a substantial limitation in light of the accumulating evidence on the importance of the immune response in tumor progression and metastasis [69].…”

Section: Discussionmentioning

confidence: 99%

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Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells

et al. 2017

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BackgroundThe development and progression of estrogen receptor alpha positive (ERα+) breast cancer has been linked epidemiologically to prolactin. However, activation of the canonical mediator of prolactin, STAT5, is associated with more differentiated cancers and better prognoses. We have reported that density/stiffness of the extracellular matrix potently modulates the repertoire of prolactin signals in human ERα + breast cancer cells in vitro: stiff matrices shift the balance from the Janus kinase (JAK)2/STAT5 cascade toward pro-tumor progressive extracellular regulated kinase (ERK)1/2 signals, driving invasion. However, the consequences for behavior of ERα + cancers in vivo are not known.MethodsIn order to investigate the importance of matrix density/stiffness in progression of ERα + cancers, we examined tumor development and progression following orthotopic transplantation of two clonal green fluorescent protein (GFP) + ERα + tumor cell lines derived from prolactin-induced tumors to 8-week-old wild-type FVB/N (WT) or collagen-dense (col1a1 tm1Jae/+) female mice. The latter express a mutant non-cleavable allele of collagen 1a1 “knocked-in” to the col1a1 gene locus, permitting COL1A1 accumulation. We evaluated the effect of the collagen environment on tumor progression by examining circulating tumor cells and lung metastases, activated signaling pathways by immunohistochemistry analysis and immunoblotting, and collagen structure by second harmonic generation microscopy.ResultsERα + primary tumors did not differ in growth rate, histologic type, ERα, or prolactin receptor (PRLR) expression between col1a1 tm1Jae/+ and WT recipients. However, the col1a1 tm1Jae/+ environment significantly increased circulating tumor cells and the number and size of lung metastases at end stage. Tumors in col1a1 tm1Jae/+ recipients displayed reduced STAT5 activation, and higher phosphorylation of ERK1/2 and AKT. Moreover, intratumoral collagen fibers in col1a1 tm1Jae/+ recipients were aligned with tumor projections into the adjacent fat pad, perpendicular to the bulk of the tumor, in contrast to the collagen fibers wrapped around the more uniformly expansive tumors in WT recipients.ConclusionsA collagen-dense extracellular matrix can potently interact with hormonal signals to drive metastasis of ERα + breast cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0801-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

“…Hormonally responsive mouse models of breast cancer are rare [31, 32]. The neu-related lipocalin-prolactin (NRL-PRL) transgenic mouse mimics the local PRL synthesis in the mammary glands of women.…”

Section: Introductionmentioning

confidence: 99%

Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells

et al. 2017

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“…Especially in view of the extensive use of rodent models for investigations of physiological and pathogenic processes involving the estrogen receptor [68–70], the lack of 3D structures for the mouse and rat ERα-LBDs constituted a highly significant knowledge gap that needed to be filled.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, our use of in silico mutagenesis as a technique for creating homology models could easily be extended to the study of mutant receptors in breast cancer and other diseases [68, 70, 89–92]. In addition, the technique of in silico mutagenesis could be used for the rational design of estrogen receptors with substantially altered ligand affinities for applications in assays and biosensors [93].…”

Section: Discussionmentioning

confidence: 99%

Homology models of mouse and rat estrogen receptor-α ligand-binding domain created by in silico mutagenesis of a human template: Molecular docking with 17β-estradiol, diethylstilbestrol, and paraben analogs

Gonzalez

Rae

Colacino

et al. 2019

Computational Toxicology

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Crystal structures exist for human, but not rodent, estrogen receptor-α ligand-binding domain (ERα-LBD). Consequently, rodent studies involving binding of compounds to ERα-LBD are limited in their molecular-level interpretation and extrapolation to humans. Because the sequences of rodent and human ERα-LBDs are > 95% identical, we expected their 3D structures and ligand binding to be highly similar. To test this hypothesis, we used the human ERα-LBD structure (PDB 3UUD) as a template to produce rat and mouse homology models. Employing the rodent models and human structure, we generated docking poses of 23 Group A ligands (17ß-estradiol, diethylstilbestrol, and 21 paraben analogs) in AutoDock Vina for interspecies comparisons. Ligand RMSDs (Å) (median, 95% CI) were 0.49 (0.21–1.82) (human-mouse) and 1.19 (0.22–1.82) (human-rat), well below the 2.0–2.5 Å range for equivalent docking poses. Numbers of interspecies ligand-receptor residue contacts were highly similar, with Sorensen Sc (%) = 96.8 (90.0–100) (human-mouse) and 97.7 (89.5–100) (human-rat). Likewise, numbers of interspecies ligand-receptor residue contacts were highly correlated: Pearson r = 0.913 (human-mouse) and 0.925 (human-rat). Numbers of interspecies ligand-receptor atom contacts were even more tightly correlated: r = 0.979 (human-mouse) and 0.986 (human-rat). Pyramid plots of numbers of ligand-receptor atom contacts by residue exhibited high interspecies symmetry and had Spearman rs = 0.977 (human-mouse) and 0.966 (human-rat). Group B ligands included 15 ring-substituted parabens recently shown experimentally to exhibit decreased binding to human ERα and to exert increased antimicrobial activity. Ligand efficiencies calculated from docking ligands into human ERα-LBD were well correlated with those derived from published experimental data (Pearson partial rp = 0.894 and 0.918; Groups A and B, respectively). Overall, the results indicate that our constructed rodent ERα-LBDs interact with ligands in like manner to the human receptor, thus providing a high level of confidence in extrapolations of rodent to human ligand-receptor interactions.

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“…The aggression and lack of estrogen responsiveness of the ER+ carcinomas in NRL-PRL mice resembles clinical luminal B breast cancers [77-79]. Since few mouse models develop ERα+ tumors (for reviews, [80-82]), the characteristics of the NRL-PRL tumors suggest that they are useful models of aggressive ERα+ clinical disease.…”

Section: 4 Nrl-prl Modelmentioning

confidence: 99%

Modeling Prolactin Actions in Breast Cancer In Vivo: Insights from the NRL-PRL Mouse

O’Leary

Shea

Schuler

2014

Advances in Experimental Medicine and Biology

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Elevated exposure to prolactin is epidemiologically associated with an increased risk of aggressive ER+ breast cancer. To understand the underlying mechanisms and crosstalk with other oncogenic factors, we developed the NRL-PRL mouse. In this model, mammary expression of a rat prolactin transgene raises local exposure to prolactin without altering estrous cycling. Nulliparous females develop metastatic, histotypically diverse mammary carcinomas independent from ovarian steroids, and most are ER+. These characteristics resemble the human clinical disease, facilitating study of tumorigenesis, and identification of novel preventive and therapeutic approaches.

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Genetically engineered ERα-positive breast cancer mouse models

Cited by 33 publications

References 104 publications

Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells

Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells

Homology models of mouse and rat estrogen receptor-α ligand-binding domain created by in silico mutagenesis of a human template: Molecular docking with 17β-estradiol, diethylstilbestrol, and paraben analogs

Modeling Prolactin Actions in Breast Cancer In Vivo: Insights from the NRL-PRL Mouse

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