Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan; Department of Molecular and Functional Dynamics, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Department of Molecular and Functional Dynamics, Graduate School of Medicine, Tohoku University, Sendai, Japan.
J Steroid Biochem Mol Biol. 2020 Jul;201:105698. doi: 10.1016/j.jsbmb.2020.105698. Epub 2020 May 11.
Estrogen receptor (ER)α and the human epidermal growth factor receptor (HER) family are inversely expressed in ERα-positive cancer in association with resistance to hormonal therapy, but the mechanism underlying their relationship remains unknown. We analyzed the effect of HER family ligands on the expression of ER and the HER family in ERα-positive MCF-7 and T47D breast cancer cell lines in 3D spheroid culture. Here, we demonstrated for the first time that heregulin-1β (HRG), a HER3 and HER4 ligand, most effectively regulated ER/HER family expression by decreasing ERα mRNA expression and increasing HER family mRNA expression. HRG treatment attenuated fulvestrant-mediated growth inhibition, and promoted the migration of MCF-7 cells. Moreover, HRG increased the CD44/CD24 cell fraction and side population cells, both of which are recognized as prospective breast cancer stem cell markers. HRG activated both phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and mitogen-activated protein kinase (MAPK) pathways. Inhibitors of these pathways reduced the growth of MCF-7 cells, but the addition of HRG has different effects on these pathways. HRG blocked the inhibitory effect of mTOR inhibitors, such as rapamycin and everolimus, on cell growth but not that of a PI3K inhibitor. Furthermore, HRG slightly decreased the inhibitory effect of an AKT inhibitor on cell growth. In contrast, HRG enhanced the MEK inhibitor-induced inhibition of cell growth. These findings suggest that HRG-stimulated signaling pathways allow ERα-positive breast cancer cells to escape from growth inhibition caused by everolimus, via MAPK signaling and/or other signaling pathways. Everolimus improves progression-free survival in combination with exemestane as second-line therapy for metastatic hormone receptor-positive breast cancer. Our study suggests that HRG is a novel target for ERα-positive breast cancer therapy.
雌激素受体 (ER)α 和人类表皮生长因子受体 (HER) 家族在 ERα 阳性癌症中呈相反表达，与激素治疗耐药有关，但它们之间关系的机制尚不清楚。我们分析了 HER 家族配体对 ERα 阳性 MCF-7 和 T47D 乳腺癌细胞系在 3D 球体培养中的 ER 和 HER 家族表达的影响。在这里，我们首次证明，HER3 和 HER4 配体之一的人表皮生长因子样神经生长因子 1β（HRG）通过降低 ERα mRNA 表达和增加 HER 家族 mRNA 表达来最有效地调节 ER/HER 家族表达。HRG 处理减弱了氟维司群介导的生长抑制，并促进了 MCF-7 细胞的迁移。此外，HRG 增加了 CD44/CD24 细胞群和侧群细胞，这两者都被认为是潜在的乳腺癌干细胞标志物。HRG 激活了磷脂酰肌醇 3-激酶/AKT/雷帕霉素哺乳动物靶蛋白（PI3K/AKT/mTOR）和丝裂原活化蛋白激酶（MAPK）途径。这些途径的抑制剂减少了 MCF-7 细胞的生长，但 HRG 对这些途径有不同的影响。HRG 阻断了 mTOR 抑制剂（如雷帕霉素和依维莫司）对细胞生长的抑制作用，但不阻断 PI3K 抑制剂的作用。此外，HRG 略微降低了 AKT 抑制剂对细胞生长的抑制作用。相比之下，HRG 增强了 MEK 抑制剂诱导的细胞生长抑制。这些发现表明，HRG 刺激的信号通路使 ERα 阳性乳腺癌细胞能够通过 MAPK 信号转导和/或其他信号通路逃避依维莫司引起的生长抑制。依维莫司与依西美坦联合作为转移性激素受体阳性乳腺癌的二线治疗可改善无进展生存期。我们的研究表明，HRG 是 ERα 阳性乳腺癌治疗的一个新靶点。
