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.

项目概要 最具侵袭性的雌激素受体阳性 (ER+) 乳腺癌 (BC) 病例是在年轻人中诊断出来的 女性（<50 岁）。该项目专注于一种尚未充分研究、具有攻击性且具有治疗抵抗性的形式 ER+ BC 的特征是主要是 ER+ 管腔癌细胞，散布着罕见的细胞簇 表达基础细胞角蛋白 5 (CK5) 的 ER 阴性干细胞/祖细胞。患有这种混合“发光”的患者 基底乳腺癌（LBBC）表型代表了一个以前未被识别的人群，其预后不良 预后。这些肿瘤由于其固有的不依赖于内质网的内分泌逃逸途径而具有侵袭性， 涉及 ER-/CK5+ 癌细胞群响应抗雌激素疗法而快速扩增。 我们的数据显示，LBBC 与 basal-like BC（一种 BC）具有年轻的年龄分布和攻击性特征 与早孕但没有母乳喂养相关的亚型——更普遍的因素 黑人和贫困女性之间的差异，因此可能有助于解释 BC 省的差异。有趣的是，类似基底的特征 LBBC 的发生受到妊娠激素黄体酮的促进，并受到泌乳激素的抑制 激素催乳素。令人信服的试点数据表明孕激素或抗雌激素扩大了治疗范围 通过 WNT11-PLZF-BCL6 依赖性信号传导，LBBC 中具有耐药性 CK5+ 干/祖细胞群 网络并被催乳素逆转。 拟议的研究将从机制上测试 WNT11-PLZF-BCL6 信号传导的一般要求 抗雌激素和孕激素驱动的 CK5+ 细胞群和 LBBC 扩张所需的网络 进展（目标 1）。由于 CK5+ 细胞群在未经治疗的肿瘤中通常很少见，因此更可靠的诊断 将开发 LBBC 而非单独 CK5 的分类器（目标 2）。最后，努力探索有针对性的成效 在临床前模型中破坏体内信号网络的药物，为新的治疗方法提供理论依据 LBBC 策略（目标 3）。总之，我们将机械地验证一个新发现的促进途径 治疗耐药的LBBC表型，开发更好的诊断方法，并探索治疗策略 克服这些肿瘤的内分泌抵抗。该项目具有取得高影响力进展的潜力，可以 有助于降低乳腺癌死亡率和发病率。