Intermittent Ruxolitinib to Target STATS Activation for Breast Cancer Prevention

该提案的总体目标是测试乳腺癌预防的新概念。从理论上讲，降低乳腺癌发病率可以对挽救生命和减少巨额治疗费用产生深远影响。抗雌激素可以预防乳腺癌，但它们需要长期治疗，并可能有显着的副作用。因此，迫切需要不需要多年连续治疗的新的预防性治疗。乳腺癌前病变有时但不总是进展为浸润性癌-导致这一小部分癌前病变进展的原因尚不清楚。对几种组织类型的研究表明，由于癌基因过表达和癌基因诱导的异常增殖，在人类癌前病变中细胞凋亡被激活，为恶性进展提供了屏障。必须克服这一障碍，才能使早期病变发展为全面的癌症。在我们使用小鼠模型的初步研究中，我们发现Jak 2-STAT 5信号传导可能是打破这种抗癌屏障的关键途径。因此，我们假设人类癌前病变中的JAK 2-STAT 5通路通过降低细胞凋亡抗癌屏障促进恶性进展;如果是这样，抑制这种促生存通路可以减少乳腺癌前病变的负荷，从而降低乳腺癌风险。我们预测，即使在早期病变中短暂或间歇性抑制该通路也可以使其失活并降低浸润性乳腺癌的风险，而可能的不良反应，成本和对女性的不便都很小。三个目标如下：目标1：确定STAT 5激活是否加速乳腺癌相关主要致癌事件诱导的癌前病变的肿瘤发生。目标二：确定在啮齿动物模型中短期或间歇性给予ruxolitinib是否会导致pSTAT 5表达早期病变的细胞凋亡，并有效防止其进展为癌症。目标3：确定在需要随后手术切除的核心活检的癌前病变的女性中，短期ruxolifinib是否阻断pSTAT 5并诱导病变中的细胞凋亡。

The overall goal of this proposal is to test a novel concept in breast cancer prevention. Reducing breast cancer incidence can theoretically have a profound impact on saving lives and reducing the huge cost of treatment. Antiestrogens can prevent breast cancer, but they require prolonged treatment and can have significant side effects. Therefore, new preventive therapy that does not require years of continuous treatment is urgently needed. Premalignant lesions of the breast sometimes but not always progress to invasive cancer - what causes this small subset of premalignant lesions to progress is not yet known. Studies in several tissue types indicate that apoptosis is activated in human premalignant lesions as a result of oncogene overexpression and oncogene-induced aberrant proliferation, providing a barrier to progression to malignancy. This barrier must be overcome for early lesions to develop into full-blown cancer. In our preliminary studies using mouse models, we have found that Jak2-STAT5 signaling may be a key pathway that can break this anticancer barrier. Therefore, we hypothesize that the JAK2-STAT5 pathway in human premalignant lesions promotes the progression to malignancy by lowering the apoptosis anticancer barrier; if so, inhibition of this prosurvival pathway could reduce the load of premalignant lesions in the breast and thus lower breast cancer risk. We predict that even transient or intermittent inhibition of this pathway in early lesions could devitalize them and lower the risk of invasive breast cancer, while the possible adverse effects, cost, and inconvenience to women would be small. Three aims are as follows: Aim 1: Determine if STAT5 activation accelerates tumorigenesis of premalignant lesions induced by major oncogenic events associated with breast cancer. Aim 2: Determine whether in rodent models short-term or intermittent administration of ruxolitinib causes apoptosis in pSTAT5-expressing early lesions and effectively prevents their progression to cancer. Aim 3: Determine whether in women with a premalignant lesion on core biopsy requiring subsequent surgical resection, short-term ruxolifinib blocks pSTAT5 and induces apoptosis in the lesion.