Mechanisms of Annexin A6 Mediated Basal-like Breast Cancer Progression

项目摘要 三重阴性乳腺癌(TNBC)由于其异质性、差异性，仍然是一个复杂的未得到满足的医疗需求。 预后及其迅速生长和/或转移的潜力，特别是在治疗干预之后。这个 TNBCs对包括酪氨酸激酶抑制剂(TKIs)在内的各种治疗干预的反应通常是 可怜。我们已发表的和正在进行的研究表明，钙离子依赖的膜结合Annexin A6 (AnxA6)在广泛的细胞功能中，包括定义肿瘤进展的细胞生长和运动， 转移和化疗耐药。我们现在已经证明AnxA6在TNBC中是一种肿瘤抑制因子，并且 低AnxA6的促肿瘤作用和高AnxA6的TNBC细胞的促侵袭功能 至少部分是通过AnxA6调节钙离子内流和激活GRF2。AnxA6-Low BUT的慢性治疗 具有TKI的非AnxA6高TNBC细胞导致AnxA6表达上调和晚期胆固醇积累 作为AnxA6低TNBCs对这些药物获得性耐药的一种新机制。此外， AnxA6在TNBC中的表达下调与非TNBC相比更相关，可作为一种可靠的 作为化疗反应的生物标志物和化疗后TNBC复发的独立预测因素。 有趣的是，AnxA6和GRF2的相互表达在临床上是相关的，并且是半定量的 对GRF2/AnxA6比值的评估可用于区分高侵袭性TNBCs的快速生长。 综上所述，这表明AnxA6在TNBC的进展、转移和耐药中发挥关键作用。 治疗干预，但慢性TKI诱导重新激活和促进- AnxA6在TNBC中的侵袭特性仍然知之甚少。我们假设亲侵入性的特性 AnxA6通过AnxA6调节的相互作用，由AnxA6胞外和/或胞内池介导 GRF2与Rho GTP酶结合；AnxA6表达的重新激活是通过抑制钙动员来触发的 通过有效地抑制钙离子进入通道和/或修饰特定的组蛋白标记而激活RTKs。为了测试这一点，我们 将确定TKI诱导AnxA6重新激活的机制以及AnxA6的影响 在目标1中，TNBC进展和转移中的重新激活；在目标2中，我们将确定其机制 AnxA6在基底样TNBC中的亲侵袭特性。来自这项研究的数据将导致更好的 了解TNBC细胞如何通过TKI规避慢性治疗的影响而变得更多 侵袭性和/或侵袭性是与TNBC患者死亡率相关的关键属性。

Project Summary Triple negative breast cancer (TNBC) remains a complex unmet medical need because of its heterogeneity, poor prognosis, and its potential to grow rapidly and/or metastasize especially following therapeutic intervention. The response of TNBCs to various therapeutic interventions including tyrosine kinase inhibitors (TKIs) is generally poor. Our published and ongoing studies have implicated the Ca2+ dependent membrane binding Annexin A6 (AnxA6) in a wide range of cellular functions including cell growth and motility that define tumor progression, metastasis and chemo-resistance. We have now shown that AnxA6 is a tumor suppressor in TNBC and that the pro-tumorigenic properties of low AnxA6 and the pro-invasive functions of high AnxA6 TNBC cells are mediated at least in part, by AnxA6 modulated Ca2+ influx and activation of GRF2. Chronic treatment of AnxA6-low but not AnxA6 high TNBC cells with TKIs leads to AnxA6 upregulation and accumulation of cholesterol in late endosomes as a novel mechanism for acquired resistance of AnxA6 low TNBCs to these drugs. Furthermore, reduced expression of AnxA6 is more relevant in TNBC compared to non-TNBC and may be used as a reliable biomarker for response to chemotherapy and as an independent predictor of TNBC relapse after chemotherapy. Interestingly, the reciprocal expression of AnxA6 and GRF2 is clinically relevant and semi-quantitative assessment of the ratio of GRF2:AnxA6 can be used to delineate rapidly growing from highly invasive TNBCs. Together, this suggests that AnxA6 plays a critical role in TNBC progression, metastasis and resistance to therapeutic interventions, but the mechanisms underlying the chronic TKI induced reactivation and the pro- invasive properties of AnxA6 in TNBC remain poorly understood. We hypothesize that the pro-invasive properties of AnxA6 are mediated by extracellular and/or intracellular pools of AnxA6 via AnxA6-modulated interaction of GRF2 with Rho GTPases; and that reactivation of AnxA6 expression is triggered by inhibition of Ca2+ mobilizing RTKs via potent inhibition of Ca2+ entry channels and/or modification of specific histone marks. To test this we will determine the mechanisms underlying TKI-induced reactivation of AnxA6 and the effects of AnxA6 reactivation in TNBC progression and metastasis in Aim 1; and in Aim 2, we will determine the mechanisms underlying the pro-invasive properties of AnxA6 in basal-like TNBC. Data from this study will lead to a better understanding of how TNBC cells circumvent the effects of chronic treatment with TKIs to become even more aggressive and/or invasive, key attributes associated with TNBC patient mortality.