Mishra Rosalin, Alanazi Samar, Yuan Long, Solomon Thomas, Thaker Tarjani M, Jura Natalia, Garrett Joan T
James L. Winkle College of Pharmacy, University of Ohio, Cincinnati, Ohio, USA.
Department of Cellular and Molecular Pharmacology, Cardiovascular Research Institute, University of California, San Francisco, California, USA.
Oncotarget. 2018 Jun 12;9(45):27773-27788. doi: 10.18632/oncotarget.25576.
Recent studies have highlighted a role of HER3 in ER and HER2-driven breast cancers. We sought to investigate the role of patient-derived HER3 mutations in ER+ and HER2+ breast cancer cells using ectopic expression of HER3 mutants. We found that HER3 mutant is activating with increased cell proliferation in ER+ T47D and MCF-7 breast cancer cells lacking HER2 over-expression. Immunoblotting and receptor tyrosine kinase array results indicated that T47D and MCF-7 cells expressing HER3 had increased p-HER4 and p-HER1 expression. Our data showed that HER3 induced cell proliferation is via HER4/HER1-dependent ERK1/2 and cyclinD1 mediated pathways in ER+ cells. ERα expression is upregulated in ER+ cells expressing HER3 mutant. We noted crosstalk between ERα and HER3 in T47D cells. Several HER3 mutants (F94L, G284R, D297Y, T355I, and E1261A) acquired a gain-of-function phenotype in MCF10AHER2 cells and were resistant to lapatinib. These mutants increased HER2-HER3 heterodimerization. Knocking down HER3 from ovarian and colorectal cancers with endogenous HER3 mutations abrogated cancer cell proliferation. Overall, this study provides the first systematic assessment of how mutations in HER3 affect response of ER+ and HER2+ breast cancers to clinically relevant inhibitors and finds that HER3 mutations can be activating independent of HER2 over-expression.
最近的研究突出了HER3在雌激素受体（ER）和人表皮生长因子受体2（HER2）驱动的乳腺癌中的作用。我们试图通过异位表达HER3突变体来研究患者来源的HER3突变在ER阳性和HER2阳性乳腺癌细胞中的作用。我们发现，在未过表达HER2的ER阳性T47D和MCF-7乳腺癌细胞中，HER3突变体具有激活作用，并伴有细胞增殖增加。免疫印迹和受体酪氨酸激酶阵列结果表明，表达HER3的T47D和MCF-7细胞中磷酸化HER4（p-HER4）和磷酸化HER1（p-HER1）的表达增加。我们的数据表明，HER3诱导的细胞增殖是通过ER阳性细胞中HER4/HER1依赖的细胞外信号调节激酶1/2（ERK1/2）和细胞周期蛋白D1介导的途径实现的。在表达HER3突变体的ER阳性细胞中，雌激素受体α（ERα）的表达上调。我们注意到T47D细胞中ERα和HER3之间存在相互作用。几种HER3突变体（F94L、G284R、D297Y、T355I和E1261A）在MCF10AHER2细胞中获得了功能获得性表型，并且对拉帕替尼耐药。这些突变体增加了HER2-HER3异二聚体的形成。敲低具有内源性HER3突变的卵巢癌和结直肠癌中的HER3可消除癌细胞增殖。总体而言，本研究首次系统评估了HER3突变如何影响ER阳性和HER2阳性乳腺癌对临床相关抑制剂的反应，并发现HER3突变可以独立于HER2过表达而具有激活作用。
