The WAVE2/miR-29/Integrin-β1 Oncogenic Signaling Axis Promotes Tumor Growth and Metastasis in Triple-negative Breast Cancer.
The WAVE2/miR-29/Integrin-β1 Oncogenic Signaling Axis Promotes Tumor Growth and Metastasis in Triple-negative Breast Cancer.
复制标题
DOI：
10.1158/2767-9764.crc-22-0249
复制
发表时间：
2023-01
期刊：
影响因子：
--
通讯作者：
Sossey-Alaoui, Khalid
中科院分区：
文献类型：
--
作者：
Rana, Priyanka S.;Wang, Wei;Markovic, Vesna;Szpendyk, Justin;Chan, Ernest Ricky;Sossey-Alaoui, Khalid
乳腺癌是女性中最常见的恶性肿瘤，由于其侵袭、转移和对治疗的抵抗能力，是死亡的主要原因。乳腺癌的最具侵袭性的亚型是三阴性乳腺癌（TNBC），这是由于侵袭性和转移性以及早期诊断和预后不良。TNBC肿瘤不表达雌激素、孕激素和HER2受体，这限制了它们的靶向治疗。已知通过增加细胞运动性和上调WAVE蛋白来促进癌症侵袭和转移。虽然WAVE2对癌症进展的贡献已被充分记录，但WAVE2介导的TNBC致癌特性的调节仍在研究中，WAVE2调节此类致癌途径的分子机制也在研究中。在这项研究中，我们表明WAVE2通过调节miR-29表达在TNBC的发展、进展和转移中起着重要作用，miR-29反过来靶向整合素β 1（ITGB 1）及其下游致癌活性。相反，我们发现WAVE2的表达受miR-29的负反馈调节。在WAVE 2缺陷型TNBC细胞中外源WAVE 2的再表达导致ITGB 1表达和活性的再活化，进一步证实了WAVE 2在调节整联蛋白β 1中的特异性。总之，我们的数据确定了一种新的WAVE2/miR-29/ITGB1信号传导轴，这对TNBC中侵袭-转移级联的调节至关重要。我们的发现通过靶向WAVE2和/或其下游效应物为TNBC的治疗提供了新的治疗策略。新的WAVE2/miR-29/ITGB1信号轴的鉴定可以提供关于WAVE2如何通过ITGB1和miR-29的调节来调节TNBC肿瘤的侵袭-转移级联的新见解。
Breast cancer is the most frequently diagnosed malignancy in women and the major cause of death because of its invasion, metastasis, and resistance to therapies capabilities. The most aggressive subtype of breast cancer is triple-negative breast cancer (TNBC) due to invasive and metastatic properties along with early age of diagnosis and poor prognosis. TNBC tumors do not express estrogen, progesterone, and HER2 receptors, which limits their treatment with targeted therapies. Cancer invasiveness and metastasis are known to be promoted by increased cell motility and upregulation of the WAVE proteins. While the contribution of WAVE2 to cancer progression is well documented, the WAVE2-mediated regulation of TNBC oncogenic properties is still under investigated, as does the molecular mechanisms by which WAVE2 regulates such oncogenic pathways. In this study, we show that WAVE2 plays a significant role in TNBC development, progression, and metastasis, through the regulation of miR-29 expression, which in turn targets Integrin-β1 (ITGB1) and its downstream oncogenic activities. Conversely, we found WAVE2 expression to be regulated by miR-29 in a negative regulatory feedback loop. Reexpression of exogenous WAVE2 in the WAVE2-deficient TNBC cells resulted in reactivation of ITGB1 expression and activity, further confirming the specificity of WAVE2 in regulating Integrin-β1. Together, our data identify a novel WAVE2/miR-29/ITGB1 signaling axis, which is essential for the regulation of the invasion-metastasis cascade in TNBC. Our findings offer new therapeutic strategies for the treatment of TNBC by targeting WAVE2 and/or its downstream effectors. Identification of a novel WAVE2/miR-29/ITGB1 signaling axis may provide new insights on how WAVE2 regulates the invasion-metastasis cascade of TNBC tumors through the modulation of ITGB1 and miR-29.