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Principal Investigator: Christoforos Thomas
Organization: METHODIST HOSPITAL RESEARCH INSTITUTE
Fiscal Year: 2024
Award: $350,960
Funding agency: National Cancer Institute
Abstract
Inflammatory breast cancer (IBC) is the most lethal form of breast cancer with median survival of about 4 years
compared with more than 10 years for other forms of breast cancer. Poor prognosis is associated with the high
propensity of these tumors to develop distant metastases. Despite a higher incidence of certain molecular
alterations in IBC, genetic profiling studies have failed to identify a specific therapeutic target and there are
currently no FDA-approved targeted therapies that are unique for the disease. The majority of IBC tumors lack
estrogen receptor α (ERα) suggesting the potential of ERβ to mediate effects of estrogen in these tumors.
Unlike the oncogenic ERα, ERβ is associated with epithelial differentiation and decreased invasion in non-IBC.
To investigate whether ERβ has a similar role in IBC, we analyzed human tumor tissues and datasets. Our
findings are the first to indicate expression of ER in more than 50% of IBCs and correlation of the receptor
with better survival. To investigate whether this association reflects the ability of ERβ to inhibit metastasis, we
studied preclinical models of IBC. Knockout of ER in IBC cells promotes through cytoskeleton remodeling
migration and activates molecules such as RhoC that are associated with cell motility and metastasis in IBC.
Conversely, ligands that activate ER potentiate its anti-migratory activity. Consistent with the in vitro anti-
migratory activity, ERβ proficient cells are less metastatic than ERβ knockout cells during preliminary analysis
of orthotopic and lung colonization models of IBC. We, therefore, hypothesize that ERβ and its agonists
prevent progression and metastasis of IBC tumors. Our proposed research will: 1) determine the role of ERβ
and its agonists in progression and metastasis of IBC, 2) elucidate the mechanism of the anti-metastatic
activity of ERβ and 3) examine whether ERβ is inversely associated with metastasis in IBC. To investigate the
role of ERβ in metastasis of IBC, we will examine how the receptor alters the metastatic potential of IBC cells
and tumors in vitro and in vivo. We will also evaluate the efficacy of ERβ ligands, that are currently in clinical
trials, to inhibit metastasis of IBC xenografts ensuring that our studies will impact the clinical treatment of IBC
(Aim 1). Further, we will delineate the molecular mechanisms of ERβ action by analyzing specific pathways
that are implicated in disease progression and metastasis (Aim 2). Finally, we will analyze clinical samples to
validate the expression of ERβ in tumors and verify its inverse association with metastasis (Aim 3). By defining
the role of ERβ and its associated pathways in progression and metastasis of IBC our research will provide
insights into the biology of IBC and assist to better understand why these tumors become metastatic. Our
study will also have important clinical implications by establishing ERβ as a novel and specific therapeutic
target that benefits patients with IBC. Our findings can directly be translated into advances in clinical setting
because they will validate a new therapeutic compound, the ERβ ligands, that either alone or in combination
with other drugs can substantially repress IBC metastasis and eliminate its associated mortality.
Terms: <AKT1><AKT1 gene><Actins><Affect><Age><Agonist><Architecture><Biology><Breast Cancer><Breast Cancer Cell><Breast Cancer Patient><Breast Metastasis><Breast Tumor Patient><Cancers><Cell Adhesion><Cell Body><Cell Communication and Signaling><Cell Culture System><Cell Function><Cell Line><Cell Locomotion><Cell Migration><Cell Movement><Cell Physiology><Cell Process><Cell Signaling><CellLine><Cells><Cellular Adhesion><Cellular Function><Cellular Matrix><Cellular Migration><Cellular Motility><Cellular Physiology><Cellular Process><Clinical><Clinical Treatment><Clinical Trials><Combined Modality Therapy><Cytoskeletal System><Cytoskeleton><Data Set><Disease><Disease Progression><Disorder><Distant Cancer><Distant Metastasis><Drugs><ER-BETA><ERalpha><ERbeta><ERα><ERβ><ESR-BETA><ESR1><ESR1 gene><ESR2><ESR2 gene><ESRB><ESTRB><Engineering / Architecture><Ensure><Epithelium><Estradiol Receptor alpha><Estradiol Receptor α><Estrogen Receptor 1><Estrogen Receptor 2><Estrogen Receptor alpha><Estrogen Receptor beta><Estrogen Receptor α><Estrogen Receptor β><Estrogens><FDA approved><Foundations><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GDP Dissociation Factor><GDP Dissociation Stimulators><GDP Exchange Factors><GDP-GTP Exchange Protein><GDP-GTP Reversing Factors><GPCR><GTP GDP exchange factor><Genes><Grant><Guanine Nucleotide Exchange Factors><Guanine Nucleotide Exchange Protein><Guanine Nucleotide Releasing Factors><Guanyl-Nucleotide Exchange Factor><Guanyl-Nucleotide Releasing Factor><Heterograft><Heterologous Transplantation><Human><In Vitro><Incidence><Intracellular Communication and Signaling><Invaded><Knock-out><Knockout><Ligands><Malignant Breast Neoplasm><Malignant Neoplasms><Malignant Tumor><Mediating><Medication><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Modeling><Modern Man><Molecular><Molecular Fingerprinting><Molecular Profiling><Motility><Multimodal Therapy><Multimodal Treatment><NR3A1><NR3A2><Neoplasm Metastasis><Newly Diagnosed><Non-metastatic><Nonmetastatic><Oncogenic><Outcome><PRKBA><Pathway interactions><Patients><Pattern><Pharmaceutical Preparations><Phenotype><Phosphorylation><Pre-Clinical Model><Preclinical Models><Preventative treatment><Preventive treatment><Prognosis><Protein Phosphorylation><RAC-ALPHA><RAC-ALPHA Gene><RAC-PK-Alpha><Reagent><Receptor Activation><Receptor Protein><Reporting><Repression><Research><Research Specimen><Role><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Specimen><Strains Cell Lines><Subcellular Process><Therapeutic Estrogen><Translating><Tumor Tissue><Xenograft><Xenograft Model><Xenograft procedure><Xenotransplantation><ages><aggressive breast cancer><biological signal transduction><breast cancer metastasis><breast tumor cell><cancer metastasis><cell motility><colonization associated with lung><colonization in the lung><colonization within the lung><combination therapy><combined modality treatment><combined treatment><cultured cell line><determine efficacy><differential expression><differentially expressed><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><exchange factor><genetic profiling><improved><in vivo><inflammatory breast cancer><innovate><innovation><innovative><insight><intracellular skeleton><lung colonization><malignancy><malignant breast tumor><metastatic process><migration><molecular profile><molecular signature><mortality><multi-modal therapy><multi-modal treatment><neoplasm/cancer><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><overexpress><overexpression><pathway><pre-clinical study><preclinical study><prevent><preventing><pulmonary colonization><receptor><receptor expression><rho G-Proteins><rho GTP-Binding Proteins><rho GTPases><rho Protein P21><rho Small GTP-Binding Proteins><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><transcriptional differences><trial regimen><trial treatment><tumor><tumor cell metastasis><xeno-transplant><xeno-transplantation><xenograft transplant model><xenotransplant model>