Prolactin pathways and metastatic progression of ER-positive breast cancer

 描述（由申请方提供）：雌激素受体-a阳性（ERα+）乳腺癌（BC）占新诊断病例的70-80%。虽然对抗雌激素有潜在反应，但ERα+ BC在转移性背景下进展为抗雌激素难治性疾病是常见的。ERα+ BC亚型之间的内分泌耐药机制可能不同，涉及ERα非依赖性和ERα依赖性形式，目前仍知之甚少。催乳素（PRL）与雌激素相互作用，刺激某些ERα+ BC亚型的生长。同时，PRL-Jak-Stat 5通路促进分化并抑制BC的侵袭性特征，ERα+ BC亚组中Stat 5a信号转导的缺失与抗雌激素治疗失败相关。PRL通路参与抗雌激素难治性BC亚型的生长和进展仍有待确定。缺乏临床前人类ERα+ BC模型，其可概括从局部乳腺生长到远处转移的进展。患者来源的ERα+ BC的异种移植物在小鼠中表现出较差的摄取率。我们已经发现，小鼠PRL是一个穷人的激动剂和有效的拮抗剂的人PRL受体（PRLr）。牛PRL也是一种对人PRL r具有拮抗活性的不良激动剂。因此，已选择实验室人BC系进行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，我们在表达生理水平的循环hPRL的免疫缺陷型Nod-Scid-IL 2 R γ品系中产生hPRL敲入小鼠。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。我们建立了一组新的可连续移植的ERα+ Luminal B BC细胞系，其中几个自发转移到肺和肝。尽管ERα+持续表达，但远处转移成为抗雌激素难治性，但表现出PRL依赖性。我们的长期目标是确定抗雌激素难治性乳腺癌的机制，以改善临床管理。目的1：研究一种新发现的ERα+ BC（ERα+/CK 5+）光基底亚型。目的1在已有的ERα+实验室细胞系中探索抗雌激素难治性BC的独特的ERα非依赖性机制。我们假设在Luminobasal BC中，由于缺陷的Stat 5a驱动的分化，PRL-Stat 5信号传导的丧失促进ERα的丧失和随后的抗雌激素抗性。目的2关注管腔型B BC亚型（ERα+/CK 5-/Ki 67 high），并以我们的新型PRL依赖性患者源性异种移植物系为中心。目的2将检验以下假设：与Luminobasal BC不同，在Luminal B BC中，PRL促进转移瘤的生长和存活，并且靶向PRL r途径与抗雌激素协同作用以消除远处转移瘤。

 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.