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: 10090247
• 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/10090247
• 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; 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.

项目摘要 三阴性乳腺癌（TNBC）仍然是一个复杂的未满足的医疗需求，因为它的异质性，穷人， 预后，以及其快速生长和/或转移的潜力，特别是在治疗干预后。的 TNBC对包括酪氨酸激酶抑制剂（TKI）在内的各种治疗干预的反应通常是 扶贫我们已发表和正在进行的研究表明，钙依赖性膜结合膜联蛋白A6 （AnxA 6）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性， 转移和化学抗性。我们现在已经表明，AnxA 6是TNBC中的肿瘤抑制因子， 低AnxA 6的促肿瘤发生特性和高AnxA 6 TNBC细胞的促侵袭功能是介导的 至少部分通过AnxA 6调节Ca 2+内流和GRF 2的激活。长期治疗AnxA 6-低，但 而不是AnxA 6高TNBC细胞与TKI导致AnxA 6上调和胆固醇积累， 内体作为AnxA 6低TNBC对这些药物获得性耐药性的新机制。此外，委员会认为， 与非TNBC相比，AnxA 6的表达减少在TNBC中更相关，并且可以用作可靠的评估指标。 作为对化疗的反应的生物标志物和作为化疗后TNBC复发的独立预测因子。 有趣的是，AnxA 6和GRF 2的相互表达是临床相关的和半定量的。 GRF 2：AnxA 6比率的评估可用于描绘从高度侵袭性TNBC快速生长。 总之，这表明AnxA 6在TNBC进展、转移和抗肿瘤中起关键作用。 治疗干预，但慢性TKI诱导的再激活和促- AnxA 6在TNBC中的侵袭特性仍然知之甚少。我们假设， 通过细胞外和/或细胞内的AnxA 6池，通过AnxA 6调节的 GRF 2与Rho GTP酶的结合; AnxA 6表达的再激活是通过抑制Ca 2+动员来触发的。 RTKs通过有效抑制Ca 2+进入通道和/或修饰特异性组蛋白标记。为了验证这一点， 将确定TKI诱导的AnxA 6再激活的潜在机制以及AnxA 6的作用 目的1中TNBC进展和转移中的再激活;目的2中，我们将确定其机制 这是AnxA 6在基底样TNBC中的促侵袭特性的基础。这项研究的数据将导致更好的 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，与TNBC患者死亡率相关的关键属性。