Mechanisms of Annexin A6 Mediated Basal-like Breast Cancer Progression

膜联蛋白 A6 介导基底样乳腺癌进展的机制

• 批准号: 10671501
• 负责人: Amos Malle Sakwe
• 金额: $ 36.38万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671501
• 关键词: ANXA2 gene; Annexin A6; Annexins; Attenuated; Binding; Biochemical; Biological Assay; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast cancer metastasis; Cancer Relapse; Cell physiology; Chemoresistance; Cholesterol; Chronic; Complex; Data; Degenerative polyarthritis; Development; Drug resistance; Epidermal Growth Factor Receptor; Experimental Models; Growth; Heterogeneity; Histones; Incidence; Malignant - descriptor; Mediating; Medical; Membrane; Modification; NF-kappa B; NFKB Activation Pathway; Neoplasm Metastasis; Pathway interactions; Pharmaceutical Preparations; Play; Prognosis; Property; Proteins; Publishing; Relapse; Resistance; Role; Signal Transduction; Site; Testing; Therapeutic Intervention; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; Up-Regulation; breast cancer progression; cancer invasiveness; cancer subtypes; cell growth; cell motility; chemotherapy; clinically relevant; extracellular; improved; late endosome; live cell imaging; malignant breast neoplasm; mortality; neoplastic cell; novel; p65; racial disparity; response; response biomarker; rho GTP-Binding Proteins; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression; tumorigenic

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.

项目概要 三阴性乳腺癌（TNBC）由于其异质性、较差的治疗效果，仍然是一个复杂的未满足的医疗需求。 预后，及其快速生长和/或转移的潜力，尤其是在治疗干预后。这 TNBC 对包括酪氨酸激酶抑制剂 (TKI) 在内的各种治疗干预措施的反应通常是 贫穷的。我们已发表和正在进行的研究表明 Ca2+ 依赖性膜结合膜联蛋白 A6 (AnxA6) 广泛的细胞功能，包括定义肿瘤进展的细胞生长和运动， 转移和化疗耐药性。我们现在已经证明 AnxA6 是 TNBC 中的肿瘤抑制因子，并且 低 AnxA6 的促肿瘤特性和高 AnxA6 TNBC 细胞的促侵袭功能是介导的 至少部分是通过 AnxA6 调节 Ca2+ 流入和 GRF2 激活。 AnxA6-低但长期治疗 不使用 TKI 的 AnxA6 高 TNBC 细胞会导致 AnxA6 上调和晚期胆固醇积累 内体作为 AnxA6 低 TNBC 对这些药物获得性耐药的新机制。此外， 与非 TNBC 相比，AnxA6 表达降低在 TNBC 中更相关，可用作可靠的 对化疗反应的生物标志物，并作为化疗后 TNBC 复发的独立预测因子。 有趣的是，AnxA6 和 GRF2 的相反表达具有临床相关性和半定量性 GRF2:AnxA6 比率的评估可用于描绘高度侵袭性 TNBC 的快速生长。 总之，这表明 AnxA6 在 TNBC 进展、转移和耐药性中发挥着关键作用。 治疗干预，但慢性 TKI 诱导再激活和促 AnxA6 在 TNBC 中的侵袭特性仍知之甚少。我们假设促侵入特性 AnxA6 的作用是由 AnxA6 的细胞外和/或细胞内池通过 AnxA6 调节的相互作用介导的 GRF2 与 Rho GTP 酶； AnxA6 表达的重新激活是通过抑制 Ca2+ 动员来触发的 RTK 通过有效抑制 Ca2+ 进入通道和/或修饰特定组蛋白标记。为了测试这个我们 将确定 TKI 诱导 AnxA6 重新激活的机制以及 AnxA6 的作用 目标 1 中 TNBC 进展和转移的再激活；在目标 2 中，我们将确定机制 AnxA6 在基底样 TNBC 中的促侵袭特性的基础。这项研究的数据将带来更好的结果 进一步了解 TNBC 细胞如何规避 TKI 长期治疗的影响 侵袭性和/或侵入性是与 TNBC 患者死亡率相关的关键属性。