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 最具侵袭性的雌激素受体阳性(ER+)乳腺癌(BC)是在年轻人中诊断出来的 女性(&lt；50岁)。该项目关注的是一种未被充分研究、具有攻击性和抗药性的形式。 ER+BC的特征是以ER+腔癌细胞为主，夹杂着稀有的成簇的 表达基础细胞角蛋白-5(CK5)的ER阴性干/祖细胞。患有这种混合型‘Lumino’的患者 基底乳腺癌(LBBC)表型代表了一种以前未被识别的人群，具有不良 预后。这些肿瘤具有侵袭性，是因为它们固有的ER非依赖性内分泌逃逸途径，这是 涉及ER-/CK5+癌细胞群体的快速扩张，以应对抗雌激素治疗。 我们的数据显示，LBBC的年龄分布和攻击性特征与Basal-Like BC相同 与早孕无母乳喂养相关的亚型--更普遍的因素 在黑人和较贫穷的妇女中，这可能有助于解释BC的差异。耐人寻味的是，像基底一样的特征 LBBC由孕激素黄体酮促进，而产乳素则抑制 催乳素激素。令人信服的试点数据表明，孕激素或抗雌激素扩大了治疗- LBBC中依赖WNT11-PLZF-BCL6信号的CK5+耐药干/祖细胞群 网络，并被催乳素逆转。 建议的研究将从机械上测试WNT11-PLZF-BCL6信令的一般要求 抗雌激素和孕激素驱动的CK5+细胞和LBBC扩增所需的网络 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，因此更可靠地诊断 将开发用于LBBC而不是CK5的分类器(目标2)。最后，将努力探索有针对性的疗效 在临床前模型中破坏体内这一信号网络的药物为新的治疗方法提供理论基础 LBBC战略(目标3)。总而言之，我们将机械地验证一条新发现的促进 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。