14-3-3tau drives estrogen receptor loss and breast cancer progression

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: FANG-TSYR  LIN
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $347,701
Funding agency: National Cancer Institute

Project Summary/Abstract
The objective of this project is to characterize a new therapeutic target in order to improve breast cancer therapy
by preventing breast cancer from spreading and restoring the effectiveness of hormone therapy. While estrogen
receptor (ER) is the most successful therapeutic target in breast cancer, up to one-third of breast cancers lose
ER expression and thus do not respond to hormone therapy. The mechanisms for ER loss in the majority of ER-
negative breast cancers remain to be investigated. On the other hand, despite most breast cancers are
diagnosed during relatively early stage, nearly 30% of them will eventually develop metastasis after treatment.
We have now identified 14-3-3tau as a key driver that promotes breast cancer metastasis and ER loss in vivo.
We have established a 14-3-3tau xenograft model which recapitulates metastasis and loss of estrogen receptor
expression as seen in patients with high levels of 14-3-3tau in their breast tumors. We also developed a new in
vitro 3D breast cancer spheroid model of ER loss. This proposal will investigate how 14-3-3tau promotes the
evolution of breast cancer from ER-positive to ER-negative and endocrine resistance, and use the established
3D spheroid culture and animal models to identify the drugs capable of blocking these adverse effects. Some
small molecule inhibitors for the proposed pathways have been available in clinics or been tested in clinical trials
for other conditions. Thus, if confirmed, it would be quite feasible to test them in patients with tumors harboring
high levels of 14-3-3tau, which are found in over 60% of breast cancer. Through the examination of 14-3-3tau
expression in the breast tumor samples, we might be able to identify the patients who are at risk of developing
metastasis and losing response to endocrine therapy. These patients may benefit from treatment with these
inhibitors targeting the downstream effectors of 14-3-3tau to prevent endocrine therapy resistance and
metastasis. Some of these inhibitors have already been approved for other diseases or are available in clinical
trials. Thus, the potential impact of this proposal in providing a novel therapeutic strategy to prevent breast
cancer metastasis and to reverse endocrine therapy resistance in breast cancer is very significant.

Terms: <3-D><3-Dimensional><3D><3D cell culture><3D culture><Adverse effects><After Care><After-Treatment><Aftercare><Animal Model><Animal Models and Related Studies><Binding><Biological Markers><Breast Cancer><Breast Cancer Patient><Breast Cancer Prevention><Breast Cancer therapy><Breast Metastasis><Breast Neoplasms><Breast Tumor Patient><Breast Tumors><CLG4B><Cadherin-1><Cell Body><Cell Communication and Signaling><Cell Mobility><Cell Signaling><Cells><Cellular Mobility><Characteristics><Clinic><Clinical Trials><Collaborations><Cultured Cells><Data><Disease><Disorder><Dissociation><Drugs><E-Cadherin><E2F Transcription Factor 1><E2F transcription factor 1 protein><E2F transcription factors><E2F-1><E2F-1 protein><E2F1><E2F1 gene><E2F1 protein><EGF Receptor><EGFR><ER Negative><ER Positive><ER+><ERBB Protein><ERalpha><ERα><ESR1><ESR1 gene><Effectiveness><Endocrine><Endocrine Therapy><Enhancer-Binding Protein GATA3><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Epithelial Calcium-Dependent Adhesion Protein><Epithelial-Cadherin><Epithelium><Estradiol Receptor alpha><Estradiol Receptor α><Estrogen Receptor 1><Estrogen Receptor alpha><Estrogen Receptor α><Estrogen Receptors><Estrogen receptor negative><Estrogen receptor positive><Event><Evolution><Exons><GATA-3 factors><GATA-3 protein><GATA-Binding Protein 3><GATA3><GATA3 gene><GATA3 protein><GATA3 transcription factor><GELB><GTP Phosphohydrolases><GTPases><Gene Transcription><Genetic Transcription><Guanosine Triphosphate Phosphohydrolases><Guanosinetriphosphatases><HER1><Heterograft><Heterologous Transplantation><Hormonal Therapy><In Vitro><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Invaded><Investigation><Isoforms><MCF-7><MCF-7 Cell><MCF-7DR><MCF-7WT><MCF7><MCF7 cell><MDA MB 231><MDA-231><MDA-MB231><MMP9><MMP9 gene><Malignant Breast Neoplasm><Mammary Cancer><Mammary Neoplasms><Mediating><Medication><Mesenchymal><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Modeling><Molecular Interaction><NR3A1><Neoplasm Metastasis><PBR3><PRB-Binding Protein E2F-1><Pathway interactions><Patients><Pharmaceutical Preparations><Pharmacologic Actions><Phenocopy><Protein Isoforms><RBAP-1><RBBP-3><RBBP3><RBP3><RNA Expression><Regulation><Resistance><Retinoblastoma Binding Protein 3><Retinoblastoma-Associated Protein 1><Risk><Role><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><TGF-alpha Receptor><Testing><Transcription><Transforming Growth Factor alpha Receptor><Up-Regulation><Upregulation><Urogastrone Receptor><Uvomorulin><Vimentin><Xenograft><Xenograft Model><Xenograft procedure><Xenotransplantation><bio-markers><biologic marker><biological signal transduction><biomarker><breast cancer diagnosis><breast cancer metastasis><breast cancer progression><c-erbB-1><c-erbB-1 Protein><cancer metastasis><cancer microenvironment><clinical relevance><clinically relevant><derepression><drug/agent><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><guanosinetriphosphatase><high risk><hormone therapy><improved><in vivo><in vivo Model><inhibitor><innovate><innovation><innovative><interventional strategy><malignant breast tumor><mammary cancer prevention><mammary tumor><mammary tumor prevention><migration><model of animal><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapeutics><new therapy><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><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 approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><overexpress><overexpression><pathway><pharmacologic><post treatment><prevent><prevent breast cancer><preventing><promoter><promotor><protein expression><proto-oncogene protein c-erbB-1><receptor expression><resistant><response><shRNA><short hairpin RNA><slug><small hairpin RNA><small molecular inhibitor><small molecule inhibitor><social role><spheroids><therapeutic target><three dimensional><three dimensional cell culture><transcription factor E2F1><tumor><tumor cell metastasis><tumor microenvironment><xeno-transplant><xeno-transplantation><xenograft transplant model><xenotransplant model>