Falcone Italia, Giontella Elena, Giuliani Stefano, Borghesani Giulia, Valenti Alessandro, Zambonin Valentina, Monteverdi Sara, Carbognin Luisa, Bria Emilio, Ciuffreda Ludovica, Conciatori Fabiana, Bazzichetto Chiara, Pedron Serena, Nottegar Alessia, Zanelli Sara, Muzzarelli Alice, Fabi Alessandra, Migliaccio Silvia, Ferretti Elisabetta, Bei Roberto, Fiorio Elena, Fanciulli Maurizio, Sperduti Isabella, Caliò Anna, Milella Michele
SAFU, Department of Research, Advanced Diagnostics, and Technological Innovation, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy.
Section of Innovation Biomedicine-Oncology Area, Department of Engineering for Innovation Medicine, University of Verona and Verona University and Hospital Trust (AOUI), 37134 Verona, Italy.
Int J Mol Sci. 2025 Jul 9;26(14):6593. doi: 10.3390/ijms26146593.
Mechanistic relationships between heat shock protein 90 (HSP90) and human epidermal growth factor receptor 2 (HER2) are complex and clinical correlations in breast cancer remain inconsistent. We investigated the role of HSP90 expression in the response of breast cancer cells to HER2-targeted treatments, by measuring cell viability/proliferation and protein expression after genetic and pharmacologic HER2/HSP90 modulation. HSP90 expression was also assessed by immunohistochemistry in a series of 72 metastatic, HER2+ breast cancer patients. In HER2+ breast cancer models (AU565, BT474, MCF7-HER2), HER2 downregulation induced HSP90 upregulation and growth inhibitory synergism between trastuzumab and docetaxel. HSP90 downregulation blunted the response to trastuzumab and docetaxel and their synergistic interactions. The addition of pertuzumab caused little additional growth inhibition, but HSP90 silencing unmasked a synergistic growth inhibitory effect with the triple combination. Conversely, HSP90 downregulation blunted the therapeutic response to trastuzumab/pertuzumab/tamoxifen or trastuzumab-emtansine. In HER2+ breast cancer patients, high HSP90 expression was associated with significant progression-free survival benefit with the triple combination, as compared with trastuzumab and chemotherapy, although the interaction test was not statistically significant. Overall, our results highlight a mechanistic role for HSP90 in determining the response of breast cancer cells to HER2-targeted agents and suggest that trastuzumab/pertuzumab combinations may be particularly advantageous in HSP90-high, HER2+ breast cancer.
热休克蛋白90（HSP90）与人类表皮生长因子受体2（HER2）之间的机制关系复杂，且在乳腺癌中的临床相关性仍不一致。我们通过在基因和药理学上对HER2/HSP90进行调控后测量细胞活力/增殖和蛋白质表达，研究了HSP90表达在乳腺癌细胞对HER2靶向治疗反应中的作用。还通过免疫组织化学对72例转移性HER2阳性乳腺癌患者进行了HSP90表达评估。在HER2阳性乳腺癌模型（AU565、BT474、MCF7-HER2）中，HER2下调诱导HSP90上调以及曲妥珠单抗和多西他赛之间的生长抑制协同作用。HSP90下调减弱了对曲妥珠单抗和多西他赛及其协同相互作用的反应。添加帕妥珠单抗几乎没有额外的生长抑制作用，但HSP90沉默揭示了三联组合的协同生长抑制作用。相反，HSP90下调减弱了对曲妥珠单抗/帕妥珠单抗/他莫昔芬或曲妥珠单抗-恩美曲妥珠单抗的治疗反应。在HER2阳性乳腺癌患者中，与曲妥珠单抗和化疗相比，高HSP90表达与三联组合显著的无进展生存获益相关，尽管交互检验无统计学意义。总体而言，我们的结果突出了HSP90在决定乳腺癌细胞对HER2靶向药物反应中的机制作用，并表明曲妥珠单抗/帕妥珠单抗组合在HSP90高表达的HER2阳性乳腺癌中可能特别有利。
