Ninio-Many Lihi, Hikri Elad, Burg-Golani Tamar, Stemmer Salomon M, Shalgi Ruth, Ben-Aharon Irit
Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel.
Davidoff Center, Rabin Medical Center, Institute of Oncology, Petah-Tiqva, Israel.
Front Oncol. 2020 Feb 28;10:191. doi: 10.3389/fonc.2020.00191. eCollection 2020.
The EGFR/HER2 signaling network is an effective therapeutic target for HER2-positive cancers, which are known for their aggressive biological course. Evidence indicates that the EGFR/HER2 network plays a role in the aggressive basal-like subtype as well. Here, we studied the potential role of miR-125a-3p as a modulator of the EGFR/HER2 pathway in basal-like breast cancer. Over-expression of miR-125a-3p reduced the migratory capability of MDA-MB-231 cells and led to an increase in the expression of ErbB2 transcript and protein. The induced ErbB2 responded to trastuzumab and underwent internalization and subsequent intra-lysosomal degradation. Trastuzumab treatment further reduced the migratory capability and induced the apoptosis of the cells. An mouse model, which supported the findings, showed a synergistic effect for miR-125a-3p and trastuzumab. Trastuzumab-treated miR-125a-3p-induced tumors were significantly smaller than control induced tumors. Our findings indicate that, in the basal-like subtype of breast cancer, miR-125a-3p may act as a tumor suppressor. miR-125a-3p induces an increase in the expression of ErbB2 that may render the cells suitable for treatment with anti-HER2 therapies.
表皮生长因子受体/人表皮生长因子受体2（EGFR/HER2）信号网络是HER2阳性癌症的有效治疗靶点，这类癌症以其侵袭性生物学进程而闻名。有证据表明，EGFR/HER2网络在侵袭性基底样亚型中也发挥作用。在此，我们研究了miR-125a-3p作为基底样乳腺癌中EGFR/HER2通路调节剂的潜在作用。miR-125a-3p的过表达降低了MDA-MB-231细胞的迁移能力，并导致ErbB2转录本和蛋白表达增加。诱导产生的ErbB2对曲妥珠单抗有反应，发生内化并随后在溶酶体内降解。曲妥珠单抗治疗进一步降低了细胞的迁移能力并诱导细胞凋亡。一个支持这些发现的小鼠模型显示，miR-125a-3p与曲妥珠单抗有协同作用。经曲妥珠单抗治疗的miR-125a-3p诱导肿瘤明显小于对照诱导肿瘤。我们的研究结果表明，在乳腺癌的基底样亚型中，miR-125a-3p可能作为一种肿瘤抑制因子。miR-125a-3p诱导ErbB2表达增加，这可能使细胞适合用抗HER2疗法进行治疗。
