PO.MCB07.04 · 分子与细胞生物学
瘦素驱动的三阴性乳腺癌转录重编程：探索种族差异的生物学驱动因素
Leptin-driven transcriptional reprogramming in triple-negative breast cancer: Exploring biological drivers of racial disparities
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摘要 Abstract
中文摘要
我们最近证明，肥胖是被诊断为三阴性和Luminal A亚型乳腺癌（BC）的一个重要风险因素，尤其是在黑人女性中。此外，肥胖与黑人女性更早的疾病发病相关，这些女性还表现出血清瘦素（一种肥胖相关激素）水平升高，其也显示出类似的流行病学关联。在本研究中，我们通过对源自白人（MDA-MB-231）和黑人（MDA-MB-468）患者的两种三阴性乳腺癌（TNBC）细胞系进行mRNA测序，随后进行生物信息学和通路分析，以鉴定差异表达基因（DEGs）及其对生物学通路的影响，从而研究瘦素诱导的转录组改变。瘦素处理导致广泛的基因表达改变，在MDA-MB-231中鉴定出1,857个DEGs，在MDA-MB-468细胞中鉴定出1,242个DEGs（P<0.05）。在这些DEGs中，MDA-MB-231和MDA-MB-468分别有1030个和827个上调，617个和625个下调。MDA-MB-231与MDA-MB-468之间的DEGs比较显示仅有177个DEGs为共同改变，提示瘦素信号具有多样化且细胞系特异性的转录影响。有趣的是，对载体处理的MDA-MB-231和MDA-MB-468细胞测序读段的比较，在两个细胞系之间鉴定出显著的转录本水平差异。在瘦素处理的MDA-MB-231细胞中，KEGG通路分析揭示了剪接体、类固醇生物合成、蛋白输出和基础转录因子通路的富集，同时伴随AMPK信号、粘着斑、寿命调控和胰岛素信号的抑制。相反，在MDA-MB-468细胞中，瘦素诱导了ECM-受体相互作用、Notch、PI3K-AKT以及癌症中转录失调通路的激活，同时下调氧化磷酸化、mRNA监视、TCA循环和AMPK信号。总之，这些发现提示瘦素在TNBC中诱导独特的、细胞系特异性的转录重编程，激活增殖信号通路，同时抑制能量感应和代谢调控网络。总体而言，我们的研究强调，靶向瘦素驱动的通路可能提供新的治疗和预防机会，以减轻肥胖相关的早发侵袭性乳腺癌风险。
查看英文原文 English abstract
We recently demonstrated that obesity is a significant risk factor for breast cancer (BC) diagnosis with triple-negative and Luminal A subtypes, especially in Black women. Furthermore, obesity was linked to earlier disease onset in Black women, who also demonstrated elevated serum leptin levels, an obesity-associated hormone, that showed a similar epidemiologic association. In this study, we investigated leptin-induced transcriptomic alterations in two triple-negative breast cancer (TNBC) cell lines derived from White (MDA-MB-231) and Black (MDA-MB-468) patients by performing mRNA sequencing, followed by bioinformatic and pathway analyses to identify differentially-expressed genes (DEGs) and their impact on biological pathways. Leptin treatment resulted in widespread gene expression alterations, with 1,857 DEGs identified in MDA-MB-231 and 1,242 DEGs in MDA-MB-468 cells (P < 0.05). Of these DEGs, 1030 and 827 were upregulated, and 617 and 625 were downregulated in MDA-MB-231 and MDA-MB-468, respectively. A comparison of DEGs between MDA-MB-231 and MDA-MB-468 showed only 177 DEGs to be commonly altered, suggesting a diverse and cell line-specific transcriptional impact of leptin signaling. Interestingly, the comparison of sequencing reads from vehicle-treated MDA-MB-231 and MDA-MB-468 cells identified significant transcript-level differences between the two lines. In leptin-treated MDA-MB-231 cells, KEGG pathway analysis revealed enrichment of the spliceosome, steroid biosynthesis, protein export, and basal transcription factor pathways, accompanied by suppression of AMPK signaling, focal adhesion, longevity regulation, and insulin signaling. Conversely, in MDA-MB-468 cells, leptin induced the activation of the ECM-receptor interaction, Notch, PI3K-AKT, and transcriptional misregulation in cancer pathways, while downregulating oxidative phosphorylation, mRNA surveillance, the TCA cycle, and AMPK signaling. Together, these findings suggest that leptin induces distinct, cell line-specific transcriptional reprogramming in TNBC, engaging proliferative signaling pathways, while suppressing energy-sensing and metabolic regulatory networks. Overall, our study highlights that targeting leptin-driven pathways may offer novel therapeutic and preventive opportunities to mitigate the obesity-associated risk of early-onset aggressive breast cancer.
利益披露 Disclosure
S. Sudan, None..
A. Sharma, None..
S. Anand, None..
J. Kaur, None..
L. Challagundla, None..
A. Singh, None..
S. Singh, None.