Intermittent Ruxolitinib to Target STATS Activation for Breast Cancer Prevention

这项提案的总体目标是测试一种预防乳腺癌的新概念。从理论上讲，降低乳腺癌发病率可以对挽救生命和降低巨额治疗成本产生深远影响。抗雌激素可以预防乳腺癌，但它们需要长期治疗，而且可能有显著的副作用。因此，迫切需要一种不需要多年持续治疗的新的预防性疗法。乳腺癌前病变有时但不总是进展为浸润性癌症--是什么导致这一小部分癌前病变进展尚不清楚。对几种组织类型的研究表明，由于癌基因的过度表达和癌基因诱导的异常增殖，人类癌前病变中的细胞凋亡被激活，为癌变提供了障碍。这一障碍必须被克服，才能使早期病变发展成全面的癌症。在我们用小鼠模型进行的初步研究中，我们发现JAK2-STAT5信号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JAK2-STAT5通路通过降低细胞凋亡抗癌屏障而促进恶变的进展；如果是这样，抑制这一生存途径可以减少乳腺癌前病变的负荷，从而降低乳腺癌的风险。我们预测，即使在早期病变中短暂或间歇性地抑制这一途径也可以使它们失去活力，降低浸润性乳腺癌的风险，而可能的不良影响、成本和对女性的不便将是很小的。三个目的如下：目的1：确定STAT5的激活是否加速了乳腺癌相关主要致癌事件引起的癌前病变的发生。目的2：确定在啮齿动物模型中，短期或间歇给药ruxolitinib是否会导致表达pSTAT5的早期病变细胞凋亡，并有效地阻止它们向癌症的进展。目的3：确定在需要随后手术切除的核心活检中有癌前病变的妇女，短期Ruxolifinib是否阻断pSTAT5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.