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The pioneer factor PBX1 is a novel driver of metastatic progression in ER?-positive breast cancer.

ABSTRACT: Over 30% of ER? breast cancer patients develop relapses and progress to metastatic disease despite treatment with endocrine therapies. The pioneer factor PBX1 translates epigenetic cues and mediates estrogen induced ER? binding. Here we demonstrate that PBX1 plays a central role in regulating the ER? transcriptional response to epidermal growth factor (EGF) signaling. PBX1 regulates a subset of EGF-ER? genes highly expressed in aggressive breast tumours. Retrospective stratification of luminal patients using PBX1 protein levels in primary cancer further demonstrates that elevated PBX1 protein levels correlate with earlier metastatic progression. In agreement, PBX1 protein levels are significantly upregulated during metastatic progression in ER?-positive breast cancer patients. Finally we reveal that PBX1 upregulation in aggressive tumours is partly mediated by genomic amplification of the PBX1 locus. Correspondingly, ER?-positive breast cancer patients carrying PBX1 amplification are characterized by poor survival. Notably, we demonstrate that PBX1 amplification can be identified in tumor derived-circulating free DNA of ER?-positive metastatic patients. Metastatic patients with PBX1 amplification are also characterized by shorter relapse-free survival. Our data identifies PBX1 amplification as a functional hallmark of aggressive ER?-positive breast cancers. Mechanistically, PBX1 amplification impinges on several critical pathways associated with aggressive ER?-positive breast cancer.

SUBMITTER: Magnani L

PROVIDER: S-EPMC4673133 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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The pioneer factor PBX1 is a novel driver of metastatic progression in ERα-positive breast cancer.

Magnani Luca L Patten Darren K DK Nguyen Van T M VT Hong Sung-Pil SP Steel Jennifer H JH Patel Naina N Lombardo Ylenia Y Faronato Monica M Gomes Ana R AR Woodley Laura L Page Karen K Guttery David D Primrose Lindsay L Fernandez Garcia Daniel D Shaw Jacqui J Viola Patrizia P Green Andrew A Nolan Christopher C Ellis Ian O IO Rakha Emad A EA Shousha Sami S Lam Eric W-F EW Győrffy Balázs B Lupien Mathieu M Coombes R Charles RC

Oncotarget 20150901 26

Over 30% of ERα breast cancer patients develop relapses and progress to metastatic disease despite treatment with endocrine therapies. The pioneer factor PBX1 translates epigenetic cues and mediates estrogen induced ERα binding. Here we demonstrate that PBX1 plays a central role in regulating the ERα transcriptional response to epidermal growth factor (EGF) signaling. PBX1 regulates a subset of EGF-ERα genes highly expressed in aggressive breast tumours. Retrospective stratification of luminal p ...[more]

PMID: 26215677

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Project description:BackgroundEndocrine 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.MethodsLuciferase-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.ResultsAs 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.ConclusionsWe 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.

Dataset Information

The pioneer factor PBX1 is a novel driver of metastatic progression in ER?-positive breast cancer.

Publications

The pioneer factor PBX1 is a novel driver of metastatic progression in ERα-positive breast cancer.

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