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

• 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
• 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

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.

项目摘要 雌激素受体阳性（ER+）乳腺癌（BC）的最具侵略性的病例是在Young中诊断的 妇女（<50岁）。该项目的重点是一种可理解的，侵略性和耐药的形式 ER+ BC的特征是主要是ER+腔内癌细胞与稀有簇的散布 表达基本细胞角蛋白5（CK5）的ER阴性干/祖细胞。患有这种混合Lumino-的患者 碱性乳腺癌（LBBC）表型代表以前未知的人群 预后。这些肿瘤由于其固有的ER独立的内分泌逃生途径而具有侵略性 涉及响应抗雌激素疗法的ER-/CK5+癌细胞群的快速扩张。 我们的数据表明，LBBC分享了BC，BC的年龄分布和侵略性特征 与早期妊娠有关而没有母乳喂养的亚型 - 更普遍的因素 在黑人和贫穷的妇女中，可能有助于解释卑诗省的差异。有趣的是，基本的功能 LBBC的孕妇孕激素促进了lbbc，并被乳酸抑制 果素催乳素。引人注目的试点数据表明，孕激素或抗雌激素扩大了治疗 - LBBC中通过WNT11-PLZF-BCl6依赖性信号传导中的CK5+茎/祖细胞群 网络，被催乳素逆转。 拟议的研究将机械测试此WNT11-PLZF-BCl6信号的一般需求 CK5+细胞种群和LBBC的抗雌激素和孕激素驱动的扩张所需的网络 进展（目标1）。因为在未处理的肿瘤中CK5+细胞种群通常很少 LBBC的分类器将比单独开发（AIM 2）。最后，努力将探讨目标的效率 在临床前模型中破坏体内信号网络的代理，以提供新疗法的基本原理 LBBC的策略（AIM 3）。总而言之，我们将机械验证新发现的途径 耐治疗的LBBC表型，开发更好的诊断方法，并探索热策略 克服这些肿瘤的内分泌耐药性。该项目具有高影响进展的潜力 有助于降低乳腺癌的死亡率和发病率。