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WNT pathway-driven anti-estrogen therapy resistance in breast cancer

WNT 通路驱动的乳腺癌抗雌激素治疗耐药

基本信息

批准号：
10606977
负责人：
Inna Chervoneva
金额：
$ 56.51万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10606977
关键词：
Affect Age Age Distribution Age Years Antiestrogen Therapy BCL6 gene Basal Cell Biological Black race Breast Cancer Cell Breast Feeding Cell physiology Cells Cessation of life Clinical Complement Cytokeratin Data Diagnosis Diagnostic Diagnostic Procedure Disparity Endocrine Estrogen Antagonists Estrogen Receptor alpha Estrogen receptor negative Estrogen receptor positive FZD6 gene Genetic Goals Hormones Investigation Knowledge Malignant Neoplasms Maps Mediating Mediator Modeling Molecular Molecular Target Morbidity - disease rate Newly Diagnosed Pathway interactions Patients Phenotype Population Pre-Clinical Model Pregnancy Progesterone Progestins Prognosis Prolactin Proteins Public Health Refractory Disease Regulation Research Research Project Grants Resistance S100A8 gene Signal Induction Signal Transduction Specimen Tamoxifen Testing Therapeutic Up-Regulation WNT11 gene Woman ZNF145 gene accurate diagnosis breast cancer diagnosis breast cancer progression cancer cell cancer classification cancer subtypes diagnostic biomarker diagnostic tool diagnostic value genetic approach hormone therapy improved in vivo inhibitor insight lactogenesis malignant breast neoplasm molecular diagnostics mortality new therapeutic target novel novel therapeutic intervention pharmacologic pre-clinical preclinical efficacy preclinical trial prevent progenitor resistance mechanism response standard of care stem stem cell population stem cells targeted agent targeted treatment therapeutic target therapy resistant tumor young woman

项目摘要

Project Summary The most aggressive cases of estrogen receptor-positive (ER+) breast cancers (BC) are diagnosed in young women (<50 years-of-age). This project is focused on an understudied, aggressive, and therapy-resistant form of ER+ BC that is characterized by predominantly ER+ luminal cancer cells interspersed with rare clusters of ER-negative stem/progenitor cells that express the basal cytokeratin-5 (CK5). Patients with this mixed ‘lumino- basal breast cancer’ (LBBC) phenotype represent a previously unrecognized population with unfavorable prognosis. These tumors are aggressive due to their inherent ER-independent endocrine escape pathway, which involves rapid expansion of the ER-/CK5+ cancer cell population in response to antiestrogen therapies. Our data reveal that LBBC shares the younger age distribution and aggressive features of basal-like BC, a BC subtype that is associated with pregnancy at early ages without breastfeeding – factors that are more prevalent among Black and poorer women and thus may help explain disparities in BC. Intriguingly, the basal-like features of LBBC are promoted by the pregnancy hormone progesterone and suppressed by the lactogenic hormone prolactin. Compelling pilot data indicates that progestins or anti-estrogens expand the therapy- resistant CK5+ stem/progenitor cell population in LBBC through a WNT11-PLZF-BCL6-dependent signaling network and is reversed by prolactin. The proposed studies will mechanistically test the general requirement of this WNT11-PLZF-BCL6 signaling network required for antiestrogen and progesterone-driven expansion of the CK5+ cell population and LBBC progression (Aim 1). Because the CK5+ cell population is often rare in untreated tumors, more robust diagnostic classifiers for LBBC than CK5 alone will be developed (Aim 2). Finally, efforts will explore the efficacy of targeted agents to disrupt this signaling network in vivo in preclinical models to provide rationale for new therapeutic strategies for LBBC (Aim 3). In sum, we will mechanistically validate a newly discovered pathway that promotes the therapy-resistant LBBC phenotype, develop better diagnostic methods, and explore therapeutic strategies to overcome endocrine resistance of these tumors. The project holds potential for high impact progress that can help reduce breast cancer mortality and morbidity.

项目总结