Oshi Masanori, Ghasemi Farhad, Yamada Akimitsu, Yan Li, Zhang Jianmin, Abrams Scott I, Endo Itaru, Takabe Kazuaki
Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Ann Surg Oncol. 2025 Jun 21. doi: 10.1245/s10434-025-17657-3.
The Hippo signaling pathway is an evolutionarily conserved network that regulates cell proliferation, apoptosis, and stemness. It also plays an important role in tumorigenesis and cancer progression, and previous studies have indicated that Hippo signaling promotes trastuzumab resistance in breast cancer (BC). However, its clinical relevance in patients with BC remains unclear.
Clinical and transcriptomics data from two large cohorts, METABRIC and TCGA, were analyzed. A Hippo pathway score was calculated by applying Gene Set Variation Analysis to the curated Kyoto Encyclopedia of Genes and Genomes (KEGG) Hippo pathway gene set (43 genes). Patients were stratified into high and low groups based on the top tertile of Hippo pathway scores in each cohort.
High Hippo pathway scores were significantly associated with worse disease-specific survival (DSS) in HER2-positive BC. In both cohorts, the Hippo pathway score showed the largest hazard ratio (HR) for DSS in HER2-positive BC compared with YAP1 or TAZ, transcription co-activators that are key components in the Hippo pathway (HR = 2.47, p = 0.04, and HR = 41.8, p = 0.03). Breast cancers with high Hippo pathway activity were associated with enrichment of cell proliferation and metastasis-related gene sets, including epithelial-mesenchymal transition, Notch, Hedgehog, and TGF-β signaling. Moreover, high Hippo pathway scores correlated with lower infiltration of anti-cancer immune cells (Th1 cells, dendritic cells, and M1-macrophages). Notably, low Hippo pathway scores were linked to a higher pathological complete response following trastuzumab-based neoadjuvant chemotherapy (p = 0.035).
Enhanced Hippo pathway activity in HER2-positive BC is associated with worse prognoses, metastasis-related gene enrichment, and reduced anti-cancer immune cell infiltration, potentially contributing to trastuzumab resistance.
河马信号通路是一个进化上保守的网络，可调节细胞增殖、凋亡和干性。它在肿瘤发生和癌症进展中也起重要作用，先前的研究表明河马信号通路促进乳腺癌（BC）中的曲妥珠单抗耐药性。然而，其在BC患者中的临床相关性仍不清楚。
分析了来自两个大型队列METABRIC和TCGA的临床和转录组学数据。通过将基因集变异分析应用于精心策划的京都基因与基因组百科全书（KEGG）河马信号通路基因集（43个基因）来计算河马信号通路评分。根据每个队列中河马信号通路评分的上三分位数将患者分为高分组和低分组。
在HER2阳性BC中，高河马信号通路评分与更差的疾病特异性生存（DSS）显著相关。在两个队列中，与河马信号通路的关键组成部分转录共激活因子YAP1或TAZ相比，河马信号通路评分在HER2阳性BC中显示出最大的DSS风险比（HR）（HR = 2.47，p = 0.04，HR = 41.8，p = 0.03）。具有高河马信号通路活性的乳腺癌与细胞增殖和转移相关基因集的富集有关，包括上皮-间质转化、Notch、Hedgehog和TGF-β信号通路。此外，高河马信号通路评分与抗癌免疫细胞（Th1细胞、树突状细胞和M1巨噬细胞）的较低浸润相关。值得注意的是，低河马信号通路评分与基于曲妥珠单抗的新辅助化疗后更高的病理完全缓解相关（p = 0.035）。
HER2阳性BC中增强的河马信号通路活性与更差的预后、转移相关基因富集和抗癌免疫细胞浸润减少相关，可能导致曲妥珠单抗耐药。
