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: 9042998
• 负责人: HALLGEIR RUI
• 金额: $ 34.96万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 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 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042998
• 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 alpha; Estrogen Therapy; Estrogen receptor positive; Estrogens; Exhibits; Experimental Models; Failure; GATA3 gene; Genetic Engineering; Goals; Growth; Hormones; Human; Human Activities; In Vitro; Investigation; Knock-in Mouse; Laboratories; Lead; Liver; Lung; Mammary gland; Metastatic Neoplasm to the Lung; Modeling; Molecular; Monitor; Mus; Neoplasm Metastasis; Newly Diagnosed; Outcome; Pathway interactions; Patients; Pharmacology; Physiological; Population; Pre-Clinical Model; Prolactin; Prolactin Receptor; Proteins; Recruitment Activity; Refractory; Refractory Disease; Regulation; Resistance; Risk Factors; Role; Selection Bias; Serum; Signal Transduction; Site; Subgroup; Testing; Time; Transcription Repressor/Corepressor; Treatment Failure; Tumor Markers; Undifferentiated; Up-Regulation; Xenograft procedure; base; breast cancer diagnosis; cancer subtypes; cohort; expectation; humanized mouse; 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（由适用提供）：雌激素受体-A阳性（ERα+）乳腺癌（BC）代表新诊断的病例的70-80％。虽然潜在地应对抗雌激素，但在转移性环境中ERα+ BC向抗雌激素难治性疾病的进展是常见的情况。 ERα+ BC的亚型之间的内分泌耐药机制可能有所不同，并且涉及ERα非依赖性和ERα依赖性形式，这些形式保持不足。催乳素（PRL）与强度相互作用，以刺激ERα+ Bc的某些亚型的生长。同时，PRL-JAK-STAT5途径促进分化并抑制BC的侵入性特征，而ERα+ BC子组中Stat5a信号的丧失与抗雌激素治疗失败有关。 PRL途径参与抗雌激素难治性BC亚型的生长和进展尚待确定。缺乏临床前人ERα+ BC模型，这些模型将局部乳腺生长到远处转移的进展概括。患者来源的ERα+ BC的异种移植物在小鼠中表现出较差的接受率。我们发现，鼠PRL是人类PRL受体（PRLR）的潜在拮抗剂。牛Prl也是一种对人PRL的拮抗剂活性的较差的激动剂。因此，已选择实验室人类BC线以进行PRL非依赖性生长，并且可能仅代表ERα+ BC的亚型。为了解决这个问题，我们在表达循环HPRL的生理水平的免疫缺陷的NOD-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID-SCID小鼠中产生。值得注意的是，PRL人性化的小鼠显示出ERα+ BC患者衍生的异种移植物的接受率大大增加。我们建立了一个新型的串行移植ERα+ Luminal B BC线，其中几种赞助向肺和肝脏转移。不同的转移成为抗雌激素难治性目的地的持续表达ERα+，但显示出PRL依赖性。我们的远距离目标是确定BC抗雌激素难治的机制，以改善临床管理。 AIM 1专注于最近确定的ERα+BC（ERα+/CK5+）的腔体亚型。 AIM 1探讨了预先存在的ERα+实验室细胞系中抗雌激素难治性BC的独立ERα独立机制。我们假设在Luminobasal BC中，由于STAT5A驱动的分化有缺陷，PRL-STAT5信号传导的丧失促进ERα的损失以及随后的抗雌激素耐药性。 AIM 2集中在Luminal B BC亚型（ERα+/CK5-/KI67High）上，并以我们新的依赖PRL依赖的患者衍生的Xenographic系列为中心。 AIM 2将检验以下假设：与Luminobasal BC不同，PRL促进了转移的生长和存活，并且PRLR-Pathway靶向与抗雌激素的合作以消除遥远的转移。