Prolactin pathways and metastatic progression of ER-positive breast cancer

描述（由申请人提供）：雌激素受体阳性（ER +）乳腺癌（BC）占新诊断病例的70-80%。虽然可能对抗雌激素有反应，但在转移环境中，ER + BC进展为抗雌激素难治性疾病是常见的。内分泌抵抗机制可能在ER + BC亚型之间有所不同，涉及ER非依赖型和ER依赖型两种形式，目前尚不清楚。催乳素（PRL）与雌激素相互作用，刺激某些ER + BC亚型的生长。同时，PRL-Jak-Stat5通路促进BC的分化并抑制其侵袭性特征，ER + BC亚群中Stat5a信号的缺失与抗雌激素治疗失败有关。PRL通路在抗雌激素难治性BC亚型的生长和进展中的作用仍有待确定。缺乏临床前人类ER + BC模型来概括从局部乳腺生长到远处转移的过程。患者来源的ER + BC异种移植在小鼠中表现出较差的接受率。我们发现鼠PRL对人PRL受体（PRLr）是一种弱的激动剂和强的拮抗剂。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系被选择用于不依赖prl的生长，并且可能仅代表ER + BC亚型。为了解决这个问题，我们在免疫缺陷的Nod-Scid-IL2R？表达生理水平循环hPRL的菌株。值得注意的是，prl人源化小鼠对患者来源的ER + BC异种移植物的接受率大大增加。我们建立了一组连续移植的ER + Luminal B细胞系，其中一些自发转移到肺和肝脏。远端转移灶虽持续表达ER，但抗雌激素难治性，但表现出prl依赖性。我们的长期目标是确定乳腺癌抗雌激素难治性的机制，以改善临床管理。Aim 1的重点是BC的Luminobasal亚型（ER +/CK5+），并探讨了最近在已有的ER +实验室细胞系中发现的抗雌激素难治性BC的独特ER独立机制。我们假设，在Luminobasal BC中，PRL-Stat5信号的缺失促进了ER -的缺失以及stat5驱动分化缺陷导致的抗雌激素抵抗。目的2和3集中于Luminal B BC亚型（ER +/CK5-/Ki67high），并将使用依赖prl的患者来源的异种移植物系。Aim 2将验证以下假设：在Luminal B BC中，与Luminobasal BC不同，PRL促进转移瘤的生长和存活，PRL通路靶向与抗雌激素协同消除远处转移瘤。目标3将探索检测和监测潜伏残留疾病的新策略。

DESCRIPTION (provided by applicant): Estrogen receptor-� positive (ER�+) breast cancer (BC) represents 70-80% of newly diagnosed cases. While potentially responsive to anti-estrogens, progression of ER�+ BC to anti-estrogen refractory disease in the metastatic setting is a common occurrence. Endocrine resistance mechanisms may differ between subtypes of ER�+ BC and involve both ER�-independent and ER�-dependent forms that remain poorly understood. Prolactin (PRL) interacts with estrogens to stimulate growth of certain subtypes of ER�+ 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 ER�+ 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 ER�+ BC models that recapitulate progression from localized mammary gland growth to distant metastasis. Xenografts of patient-derived ER�+ 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 ER�+ BC. To address this problem, we generated hPRL knock-in mice in the immunodeficient Nod-Scid-IL2R? strain that express physiological levels of circulating hPRL. Remarkably, PRL-humanized mice display greatly increased take rate of patient-derived xenografts of ER�+ BC. We established a panel of serially transplantable ER�+ Luminal B lines, several of which spontaneously metastasize to lungs and liver. The distant metastases become anti-estrogen refractory despite continued expression of ER�, 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 Luminobasal subtype of BC (ER�+/CK5+) and explores a distinct ER�-independent mechanism of anti-estrogen refractory BC recently recognized in pre-existing ER�+ laboratory cell lines. We hypothesize that in Luminobasal BC, loss of PRL-Stat5 signaling promotes loss of ER� and subsequent anti-estrogen resistance due to defective Stat5a-driven differentiation. Aims 2 and 3 are focused on the Luminal B BC subtype (ER�+/CK5-/Ki67high) and will use 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. Aim 3 will explore novel strategies for detecting and monitoring latent residual disease.