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01-06-2020 | Metastasis | Preclinical study

Suppression of breast cancer metastasis and extension of survival by a new antiestrogen in a preclinical model driven by mutant estrogen receptors

Authors: Mary J. Laws, Yvonne Ziegler, Sayyed Hamed Shahoei, Parama Dey, Sung Hoon Kim, Mayuri Yasuda, Ben Ho Park, Kendall W. Nettles, John A. Katzenellenbogen, Erik R. Nelson, Benita S. Katzenellenbogen

Published in: Breast Cancer Research and Treatment | Issue 2/2020

Abstract

Purpose

Many human breast tumors become resistant to endocrine therapies and recur due to estrogen receptor (ERα) mutations that convey constitutive activity and a more aggressive phenotype. Here, we examined the effectiveness of a novel adamantyl antiestrogen, K-07, in suppressing the growth of breast cancer metastases containing the two most frequent ER-activating mutations, Y537S and D538G, and in extending survival in a preclinical metastatic cancer model.

Methods

MCF7 breast cancer cells expressing luciferase and Y537S or D538G ER were injected into NOD-SCID-gamma female mice, and animals were treated orally with the antiestrogen K-07 or control vehicle. Comparisons were also made with the antiestrogen Fulvestrant. The development of metastases was monitored by in vivo bioluminescence imaging with phenotypic characterization of the metastases in liver and lung by immunohistochemical and biochemical analyses.

Results

These breast cancer cells established metastases in liver and lung, and K-07 treatment reduced the metastatic burden. Mice treated with K-07 also survived much longer. By day 70, only 28% of vehicle-treated mice with mutant ER metastases were alive, whereas all K-07-treated D538G and Y537S mice were still alive. K-07 also markedly reduced the level of metastatic cell ER and the expression of ER-regulated genes.

Conclusion

The antiestrogen K-07 can reduce in vivo metastasis of breast cancers and extend host survival in this preclinical model driven by constitutively active mutant ERs, suggesting that this compound may be suitable for further translational examination of its efficacy in suppression of metastasis in breast cancers containing constitutively active mutant ERs.

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Title: Suppression of breast cancer metastasis and extension of survival by a new antiestrogen in a preclinical model driven by mutant estrogen receptors
Authors: Mary J. Laws
Yvonne Ziegler
Sayyed Hamed Shahoei
Parama Dey
Sung Hoon Kim
Mayuri Yasuda
Ben Ho Park
Kendall W. Nettles
John A. Katzenellenbogen
Erik R. Nelson
Benita S. Katzenellenbogen
Publication date: 01-06-2020
Publisher: Springer US
Keywords: Metastasis
Breast Cancer
Breast Cancer
Antiestrogens
Estrogens
Fulvestrant
Published in: Breast Cancer Research and Treatment / Issue 2/2020
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-020-05629-y

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