Prolactin pathways and metastatic progression of ER-positive breast cancer

描述(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ER�+BC对抗雌激素有潜在的反应，但在转移环境中进展为抗雌激素难治性疾病是一种常见的情况。内分泌耐药机制可能因ER�+BC亚型不同而不同，涉及ER�非依赖性和ER�依赖性两种形式，目前仍知之甚少。催乳素(PRL)与雌激素相互作用，刺激某些ER�+BC亚型的生长。同时，PRL-JAK-STAT5通路促进了BC的分化，抑制了BC的侵袭特性，ER�+BC亚群中STAT5a信号的缺失与抗雌激素治疗失败有关。PRL通路在抗雌激素耐药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进展。患者来源的ER�+BC的异种移植在小鼠中的接种率很低。我们发现，小鼠催乳素是人催乳素受体(PRLr)的弱激动剂和强有力的拮抗剂。牛催乳素也是一种对人催乳素受体有拮抗活性的弱激动剂。因此，实验室人BC系已被选择用于非催乳素依赖生长，并且可能仅代表ER�+BC亚型(S)。为了解决这个问题，我们在免疫缺陷的NOD-SCID-IL2R？中产生了hPRL敲入小鼠。表达血液中hPRL生理水平的菌株。值得注意的是，PRL人源化小鼠显著提高了患者来源的ER�+BC异种移植物的接种率。我们建立了一组可连续移植的ER�+腔B细胞系，其中几个细胞自发转移到肺和肝脏。尽管ER-�持续表达，但远处转移的肿瘤对雌激素不敏感，但表现为催乳素依赖。我们的长期目标是确定BC的抗雌激素耐药机制，以改善临床治疗。目的1重点研究Bc的发光基亚型(ER�+/CK5+)，探索最近在已有的ER�+实验室细胞系中发现的抗雌激素难治性BC的一个独特的ER�非依赖性机制。我们假设，在发光性基底BC中，PRL-STAT5信号的丢失促进了ER�的丢失，以及随后由于STAT5a驱动的缺陷分化而产生的抗雌激素抵抗。AIMS 2和3专注于腔B BC亚型(ER�+/CK5-/Ki67High)，并将使用PRL依赖的患者来源的异种移植株。目的2将验证这一假设，即在腔内B BC，不同于在光基底BC，PRL促进转移的生长和生存，并且PRLr通路靶向与抗雌激素协同作用以消除远处转移。目的3将探索检测和监测潜在残留病的新策略。

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.