由癌症幸存者的慢性压力引发的交感神经激活是肿瘤发生的新兴调节剂。此前，肾上腺素能阻断与改善三阴性乳腺癌 (TNBC) 对阿霉素 (DOX) 的反应有关，但其确切的潜在机制仍不清楚。化疗期间癌症干细胞 (CSC) 的恢复能力会促进耐药性和复发。缺氧诱导因子 1α (HIF-1α) 和 β-连环蛋白是相互交织的转录因子，可丰富 CSC，有证据表明它们的表达可以通过全身肾上腺素信号调节。在此，我们的目的是探讨使用卡维地洛 (CAR) 阻断肾上腺素受体对 DOX 的影响及其调节 CSC 克服化疗耐药性的潜力。为了实现这一目标，使用肾上腺素预孵育的 MDA-MB-231 细胞进行体外研究，并使用慢性束缚应激促进的实体瘤小鼠模型进行体内研究。结果显示，肾上腺素增加了 TNBC 的增殖，并诱导了类似 CSC 的表型转换，这一点可以通过增强的乳腺球形成来证明。这些结果与乙醛脱氢酶-1 (ALDH-1) 和 Nanog 表达水平以及 HIF-1α 和 β-连环蛋白的激增相一致。在体内，与未受应激的小鼠相比，在慢性应激下的小鼠中观察到更大的肿瘤体积。然而，使用 CAR 进行肾上腺素能阻断，通过增强细胞凋亡，增强了 DOX 对阻止 TNBC 细胞增殖和肿瘤生长的影响。 CAR 还抑制了 HIF-1α 和 β-catenin 肿瘤水平，随后抑制了 ALDH-1 和 SOX2。我们的研究揭示了 HIF-1α 在压力诱导的交感神经激活中的核心作用，通过 β-连环蛋白途径促进 CSC 富集。它还在 TNBC 中强调了对 CAR 逆转 DOX 化学耐药性能力的新颖见解。版权所有 © 2024 Attia、Hakeem、Samir、Mohammed、Elsayed、Khallaf、Essam、Amin、Abdullah、Hikmat、Hossam、Mohamed、Aboelmagd 和 Hammam。

Sympathetic activation triggered by chronic stress afflicting cancer survivors is an emerging modulator of tumorigenesis. Adrenergic blockade was previously associated with improving response to doxorubicin (DOX) in triple-negative breast cancer (TNBC), yet the precise underlying mechanisms remain obscure. The resilience of cancer stem cells (CSCs) during chemotherapy fosters resistance and relapse. Hypoxia-inducible factor-1α (HIF-1α) and β-catenin are intertwined transcriptional factors that enrich CSCs and evidence suggests that their expression could be modulated by systemic adrenergic signals. Herein, we aimed to explore the impact of adrenoreceptor blockade using carvedilol (CAR) on DOX and its potential to modulate CSCs overcoming chemoresistance. To achieve this aim, in vitro studies were conducted using adrenaline-preincubated MDA-MB-231 cells and in vivo studies using a chronic restraint stress-promoted solid tumor mouse model. Results revealed that adrenaline increased TNBC proliferation and induced a phenotypic switch reminiscent of CSCs, as evidenced by enhanced mammosphere formation. These results paralleled an increase in aldehyde dehydrogenase-1 (ALDH-1) and Nanog expression levels as well as HIF-1α and β-catenin upsurge. In vivo, larger tumor volumes were observed in mice under chronic stress compared to their unstressed counterparts. Adrenergic blockade using CAR, however, enhanced the impact DOX had on halting TNBC cell proliferation and tumor growth via enhanced apoptosis. CAR also curbed HIF-1α and β-catenin tumor levels subsequently suppressing ALDH-1 and SOX2. Our study unveils a central role for HIF-1α linking stress-induced sympathetic activation fueling CSC enrichment via the β-catenin pathway. It also highlights novel insights into CAR's capacity in reversing DOX chemoresistance in TNBC.Copyright © 2024 Attia, Hakeem, Samir, Mohammed, Elsayed, Khallaf, Essam, Amin, Abdullah, Hikmat, Hossam, Mohamed, Aboelmagd and Hammam.