Rypens Charlotte, Bertucci François, Finetti Pascal, Robertson Fredika, Fernandez Sandra V, Ueno Naoto, Woodward Wendy A, Van Golen Kenneth, Vermeulen Peter, Dirix Luc, Viens Patrice, Birnbaum Daniel, Devi Gayathri R, Cristofanilli Massimo, Van Laere Steven
Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp, Belgium.
Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Marseille, France.
NPJ Breast Cancer. 2022 Jan 18;8(1):12. doi: 10.1038/s41523-021-00379-6.
Inflammatory breast cancer (IBC) is an aggressive disease for which the spectrum of preclinical models was rather limited in the past. More recently, novel cell lines and xenografts have been developed. This study evaluates the transcriptome of an extended series of IBC preclinical models and performed a comparative analysis with patient samples to determine the extent to which the current models recapitulate the molecular characteristics of IBC observed clinically. We demonstrate that the IBC preclinical models are exclusively estrogen receptor (ER)-negative and of the basal-like subtype, which reflects to some extent the predominance of these subtypes in patient samples. The IBC-specific 79-signature we previously reported was retrained and discriminated between IBC and non-IBC preclinical models, but with a relatively high rate of false positive predictions. Further analyses of gene expression profiles revealed important roles for cell proliferation, MYC transcriptional activity, and TNFɑ/NFκB in the biology of IBC. Patterns of MYC expression and transcriptional activity were further explored in patient samples, which revealed interactions with ESR1 expression that are contrasting in IBC and nIBC and notable given the comparatively poor outcomes of ER+ IBC. Our analyses also suggest important roles for NMYC, MXD3, MAX, and MLX in shaping MYC signaling in IBC. Overall, we demonstrate that the IBC preclinical models can be used to unravel cancer cell intrinsic molecular features, and thus constitute valuable research tools. Nevertheless, the current lack of ER-positive IBC models remains a major hurdle, particularly since interactions with the ER pathway appear to be relevant for IBC.
炎性乳腺癌（IBC）是一种侵袭性疾病，过去其临床前模型的种类相当有限。最近，新型细胞系和异种移植模型已被开发出来。本研究评估了一系列扩展的IBC临床前模型的转录组，并与患者样本进行了比较分析，以确定当前模型在多大程度上重现了临床上观察到的IBC分子特征。我们证明，IBC临床前模型均为雌激素受体（ER）阴性且属于基底样亚型，这在一定程度上反映了这些亚型在患者样本中的优势地位。我们之前报道的IBC特异性79基因特征在IBC和非IBC临床前模型之间进行了重新训练和区分，但假阳性预测率相对较高。对基因表达谱的进一步分析揭示了细胞增殖、MYC转录活性以及TNFɑ/NFκB在IBC生物学中的重要作用。在患者样本中进一步探索了MYC表达和转录活性模式，结果显示其与ESR1表达的相互作用在IBC和非IBC中形成对比，鉴于ER + IBC的预后相对较差，这一点值得关注。我们的分析还表明，NMYC、MXD3、MAX和MLX在塑造IBC中的MYC信号传导方面发挥重要作用。总体而言，我们证明IBC临床前模型可用于揭示癌细胞内在分子特征，因此构成了有价值的研究工具。然而，目前缺乏ER阳性IBC模型仍然是一个主要障碍，特别是因为与ER途径的相互作用似乎与IBC相关。
