Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer
Abstract Background Endocrine therapy remains the mainstay of treatment for estrogen receptor-positive (ER+) breast cancer. Constitutively active mutations in the ligand binding domain of ERα render tumors resistant to endocrine agents. Breast cancers with the two most common ERα mutations, Y537S an...
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doaj-9662ade02114434d836902ed3ba109b62021-05-16T11:23:00ZengBMCBreast Cancer Research1465-542X2021-05-0123111210.1186/s13058-021-01431-wLasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancerMuriel Lainé0Sean W. Fanning1Ya-Fang Chang2Bradley Green3Marianne E. Greene4Barry Komm5Justyna D. Kurleto6Linda Phung7Geoffrey L. Greene8The Ben May Department for Cancer Research, The University of ChicagoDepartment of Cancer Biology, Loyola University ChicagoThe Ben May Department for Cancer Research, The University of ChicagoThe Ben May Department for Cancer Research, The University of ChicagoThe Ben May Department for Cancer Research, The University of ChicagoKomm-Sandin Pharma ConsultingThe Ben May Department for Cancer Research, The University of ChicagoThe Ben May Department for Cancer Research, The University of ChicagoThe Ben May Department for Cancer Research, The University of ChicagoAbstract Background Endocrine therapy remains the mainstay of treatment for estrogen receptor-positive (ER+) breast cancer. Constitutively active mutations in the ligand binding domain of ERα render tumors resistant to endocrine agents. Breast cancers with the two most common ERα mutations, Y537S and D538G, have low sensitivity to fulvestrant inhibition, a typical second-line endocrine therapy. Lasofoxifene is a selective estrogen receptor modulator with benefits on bone health and breast cancer prevention potential. This study investigated the anti-tumor activity of lasofoxifene in breast cancer xenografts expressing Y537S and D538G ERα mutants. The combination of lasofoxifene with palbociclib, a CDK4/6 inhibitor, was also evaluated. Methods Luciferase-GFP tagged MCF7 cells bearing wild-type, Y537S, or D538G ERα were injected into the mammary ducts of NSG mice (MIND model), which were subsequently treated with lasofoxifene or fulvestrant as single agents or in combination with palbociclib. Tumor growth and metastasis were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis. Results As a monotherapy, lasofoxifene was more effective than fulvestrant at inhibiting primary tumor growth and reducing metastases. Adding palbociclib improved the effectiveness of both lasofoxifene and fulvestrant for tumor suppression and metastasis prevention at four distal sites (lung, liver, bone, and brain), with the combination of lasofoxifene/palbociclib being generally more potent than that of fulvestrant/palbociclib. X-ray crystallography of the ERα ligand binding domain (LBD) shows that lasofoxifene stabilizes an antagonist conformation of both wild-type and Y537S LBD. The ability of lasofoxifene to promote an antagonist conformation of Y537S, combined with its long half-life and bioavailability, likely contributes to the observed potent inhibition of primary tumor growth and metastasis of MCF7 Y537S cells. Conclusions We report for the first time the anti-tumor activity of lasofoxifene in mouse models of endocrine therapy-resistant breast cancer. The results demonstrate the potential of using lasofoxifene as an effective therapy for women with advanced or metastatic ER+ breast cancers expressing the most common constitutively active ERα mutations.https://doi.org/10.1186/s13058-021-01431-wBreast cancerEndocrine resistantFulvestrantLasofoxifeneSelective estrogen receptor modulator |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Muriel Lainé Sean W. Fanning Ya-Fang Chang Bradley Green Marianne E. Greene Barry Komm Justyna D. Kurleto Linda Phung Geoffrey L. Greene |
spellingShingle |
Muriel Lainé Sean W. Fanning Ya-Fang Chang Bradley Green Marianne E. Greene Barry Komm Justyna D. Kurleto Linda Phung Geoffrey L. Greene Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer Breast Cancer Research Breast cancer Endocrine resistant Fulvestrant Lasofoxifene Selective estrogen receptor modulator |
author_facet |
Muriel Lainé Sean W. Fanning Ya-Fang Chang Bradley Green Marianne E. Greene Barry Komm Justyna D. Kurleto Linda Phung Geoffrey L. Greene |
author_sort |
Muriel Lainé |
title |
Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer |
title_short |
Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer |
title_full |
Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer |
title_fullStr |
Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer |
title_full_unstemmed |
Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer |
title_sort |
lasofoxifene as a potential treatment for therapy-resistant er-positive metastatic breast cancer |
publisher |
BMC |
series |
Breast Cancer Research |
issn |
1465-542X |
publishDate |
2021-05-01 |
description |
Abstract Background Endocrine therapy remains the mainstay of treatment for estrogen receptor-positive (ER+) breast cancer. Constitutively active mutations in the ligand binding domain of ERα render tumors resistant to endocrine agents. Breast cancers with the two most common ERα mutations, Y537S and D538G, have low sensitivity to fulvestrant inhibition, a typical second-line endocrine therapy. Lasofoxifene is a selective estrogen receptor modulator with benefits on bone health and breast cancer prevention potential. This study investigated the anti-tumor activity of lasofoxifene in breast cancer xenografts expressing Y537S and D538G ERα mutants. The combination of lasofoxifene with palbociclib, a CDK4/6 inhibitor, was also evaluated. Methods Luciferase-GFP tagged MCF7 cells bearing wild-type, Y537S, or D538G ERα were injected into the mammary ducts of NSG mice (MIND model), which were subsequently treated with lasofoxifene or fulvestrant as single agents or in combination with palbociclib. Tumor growth and metastasis were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis. Results As a monotherapy, lasofoxifene was more effective than fulvestrant at inhibiting primary tumor growth and reducing metastases. Adding palbociclib improved the effectiveness of both lasofoxifene and fulvestrant for tumor suppression and metastasis prevention at four distal sites (lung, liver, bone, and brain), with the combination of lasofoxifene/palbociclib being generally more potent than that of fulvestrant/palbociclib. X-ray crystallography of the ERα ligand binding domain (LBD) shows that lasofoxifene stabilizes an antagonist conformation of both wild-type and Y537S LBD. The ability of lasofoxifene to promote an antagonist conformation of Y537S, combined with its long half-life and bioavailability, likely contributes to the observed potent inhibition of primary tumor growth and metastasis of MCF7 Y537S cells. Conclusions We report for the first time the anti-tumor activity of lasofoxifene in mouse models of endocrine therapy-resistant breast cancer. The results demonstrate the potential of using lasofoxifene as an effective therapy for women with advanced or metastatic ER+ breast cancers expressing the most common constitutively active ERα mutations. |
topic |
Breast cancer Endocrine resistant Fulvestrant Lasofoxifene Selective estrogen receptor modulator |
url |
https://doi.org/10.1186/s13058-021-01431-w |
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