Prolactin pathways and metastatic progression of ER-positive breast cancer

催乳素通路和 ER 阳性乳腺癌的转移进展

• 批准号: 8888057
• 负责人: HALLGEIR RUI
• 金额: $ 37.31万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888057
• 关键词: Address; Adoption; Affect; Agonist; B-Cell Lymphoma 6 Protein; BCL6 gene; Basal Cell; Biochemical Genetics; Breast Cancer Model; Cattle; Cell Line; Clinical; Clinical Management; Clinical Trials; Dependence; Development; Disease; Distant; Distant Metastasis; Endocrine; Environment; Estrogen Antagonists; Estrogen Receptor 2; Estrogen Receptors; Estrogen Therapy; Estrogen receptor positive; Estrogens; Exhibits; Experimental Models; Failure; GATA3 transcription factor; Genetic Engineering; Goals; Growth; Hormones; Human; Human Activities; In Vitro; Investigation; Knock-in Mouse; Laboratories; Lead; Liver; Lung; Mammary gland; Modeling; Molecular; Monitor; Mus; Neoplasm Metastasis; Newly Diagnosed; Outcome; Pathway interactions; Patients; Physiological; Population; Pre-Clinical Model; Prolactin; Prolactin Receptor; Proteins; Refractory; Refractory Disease; Regulation; Resistance; Risk Factors; Role; Selection Bias; Serum; Signal Transduction; Site; Subgroup; Testing; Time; Transcription Repressor/Corepressor; Tumor Markers; Undifferentiated; Up-Regulation; Work; Xenograft procedure; base; breast cancer diagnosis; cohort; expectation; improved; in vivo; inhibitor/antagonist; innovation; insight; malignant breast neoplasm; mortality; novel; novel strategies; oncology; pre-clinical; preclinical study; public health relevance; resistance mechanism; response; therapy resistant; tool; tumor

 DESCRIPTION (provided by applicant): Estrogen receptor-a positive (ERα+) breast cancer (BC) represents 70-80% of newly diagnosed cases. While potentially responsive to anti-estrogens, progression of ERα+ BC to anti-estrogen refractory disease in the metastatic setting is a common occurrence. Endocrine resistance mechanisms may differ between subtypes of ERα+ BC and involve both ERα-independent and ERα-dependent forms that remain poorly understood. Prolactin (PRL) interacts with estrogens to stimulate growth of certain subtypes of ERα+ BC. At the same time, the PRL-Jak-Stat5 pathway promotes differentiation and inhibits invasive features of BC, and loss of Stat5a signaling in a subgroup of ERα+ BC is associated with anti-estrogen therapy failure. The involvement of PRL pathways in growth and progression of anti-estrogen refractory BC subtypes remains to be determined. There is a lack of preclinical human ERα+ BC models that recapitulate progression from localized mammary gland growth to distant metastasis. Xenografts of patient-derived ERα+ BC exhibit poor take rate in mice. We have discovered that murine PRL is a poor agonist and a potent antagonist for human PRL receptor (PRLr). Bovine PRL is also a poor agonist with antagonist activity for human PRLr. Laboratory human BC lines therefore have been selected for PRL-independent growth and may only represent subtype(s) of ERα+ BC. To address this problem, we generated hPRL knock-in mice in the immunodeficient Nod-Scid-IL2Rγ strain that express physiological levels of circulating hPRL. Remarkably, PRL-humanized mice display greatly increased take rate of patient-derived xenografts of ERα+ BC. We established a novel panel of serially transplantable ERα+ Luminal B BC lines, several of which spontaneously metastasize to lungs and liver. The distant metastases become anti-estrogen refractory despite continued expression of ERα+, but show PRL-dependence. Our long-range goal is to determine mechanisms of anti-estrogen refractoriness of BC to improve clinical management. Aim 1 is focused on a recently identified Luminobasal subtype of ERα+ BC (ERα+/CK5+). Aim 1 explores a distinct ERα-independent mechanism of anti-estrogen refractory BC in pre-existing ERα+ laboratory cell lines. We hypothesize that in Luminobasal BC, loss of PRL-Stat5 signaling promotes loss of ERα and subsequent anti-estrogen resistance due to defective Stat5a-driven differentiation. Aim 2 is focused on the Luminal B BC subtype (ERα+/CK5-/Ki67high) and is centered on our new PRL-dependent patient-derived xenograft lines. Aim 2 will test the hypothesis that in Luminal B BC, unlike in Luminobasal BC, PRL facilitates growth and survival of metastases and that PRLr-pathway targeting cooperates with anti-estrogens to eliminate distant metastases.

 描述（由申请人提供）：雌激素受体阳性（ERα+）乳腺癌（BC）占新诊断病例的 70-80%。虽然对抗雌激素可能有反应，但在转移环境中 ERα+ BC 进展为抗雌激素难治性疾病是常见的情况。 ERα+ BC 亚型之间的内分泌抵抗机制可能有所不同，并且涉及 ERα 独立型和 ERα 依赖性型，但目前对此仍知之甚少。催乳素 (PRL) 与雌激素相互作用，刺激 ERα+ BC 某些亚型的生长。同时，PRL-Jak-Stat5 通路促进分化并抑制 BC 的侵袭特征，ERα+ BC 亚组中 Stat5a 信号的丧失与抗雌激素治疗失败相关。 PRL 通路在抗雌激素难治性 BC 亚型的生长和进展中的参与仍有待确定。目前缺乏能够概括从局部乳腺生长到远处转移进展的临床前人类 ERα+ BC 模型。源自患者的 ERα+ BC 异种移植物在小鼠中表现出较差的接受率。我们发现，鼠 PRL 是人 PRL 受体 (PRLr) 的弱激动剂和强拮抗剂。牛 PRL 也是一种较差的激动剂，对人 PRLr 具有拮抗活性。因此，实验室人类 BC 系已被选择用于不依赖于 PRL 的生长，并且可能仅代表 ERα+ BC 的亚型。为了解决这个问题，我们在免疫缺陷的 Nod-Scid-IL2Rγ 品系中培育了 hPRL 敲入小鼠，该小鼠表达生理水平的循环 hPRL。值得注意的是，PRL 人源化小鼠显示出患者来源的 ERα+ BC 异种移植物的摄取率大大增加。我们建立了一系列可连续移植的 ERα+ Luminal B BC 系，其中一些自发转移至肺和肝。尽管 ERα+ 持续表达，但远处转移灶仍难以抗雌激素治疗，但显示出 PRL 依赖性。我们的长期目标是确定 BC 抗雌激素无效的机制，以改善临床管理。目标 1 重点关注最近发现的 ERα+ BC (ERα+/CK5+) 的 Luminobasal 亚型。目标 1 探索现有 ERα+ 实验室细胞系中抗雌激素难治性 BC 的独特的 ERα 独立机制。我们假设在 Luminobasal BC 中，PRL-Stat5 信号传导的丧失会促进 ERα 的丧失，并由于 Stat5a 驱动的分化缺陷而导致随后的抗雌激素抵抗。目标 2 专注于 Luminal B BC 亚型 (ERα+/CK5-/Ki67high)，并以我们新的 PRL 依赖性患者来源的异种移植品系为中心。目标 2 将检验以下假设：在 Luminal B BC 中，与 Luminobasal BC 不同，PRL 促进转移瘤的生长和存活，并且 PRLr 通路靶向与抗雌激素合作消除远处转移瘤。