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）病例是在年轻人中诊断出来的。 女性（50岁以下）。这个项目的重点是一个研究不足，侵略性，和治疗抗性形式 的ER+ BC，其特征在于主要是ER+管腔癌细胞，散布有罕见的成簇的 表达基底细胞角蛋白-5（CK 5）的ER阴性干/祖细胞。患有这种混合型“鲁米诺- “基底乳腺癌”（LBBC）表型代表了以前未被认识到的不利群体 预后这些肿瘤由于其固有的ER非依赖性内分泌逃逸途径而具有侵袭性， 涉及ER-/CK 5+癌细胞群体响应于抗雌激素疗法的快速扩增。 我们的数据表明，LBBC共享的年轻的年龄分布和基底样BC，一个BC的侵略性特征， 与未母乳喂养的早期怀孕相关的亚型-更普遍的因素 这可能有助于解释不列颠哥伦比亚省的差异。有趣的是， 的LBBC是促进怀孕激素孕酮和抑制催乳素 催乳激素令人信服的试点数据表明，孕激素或抗雌激素扩展了治疗- LBBC中通过WNT 11-PLZF-BCL 6依赖性信号传导的抗CK 5+干/祖细胞群 网络，并通过催乳素逆转。 所提出的研究将机械地测试这种WNT 11-PLZF-BCL 6信号传导的一般要求 抗雌激素和孕酮驱动的CK 5+细胞群和LBBC扩增所需的网络 进展（目标1）。因为CK 5+细胞群在未经治疗的肿瘤中通常是罕见的，所以更稳健的诊断可能是一个非常重要的因素。 将开发用于LBBC而不是单独的CK 5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这种体内信号传导网络的药物，为新的治疗方法提供理论基础。 LBBC战略（目标3）。总之，我们将机械地验证一个新发现的途径， 耐药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。该项目具有高影响力的进展潜力， 有助于降低乳腺癌死亡率和发病率。