|
众所周知，他莫昔芬可以抑制雌激素受体阳性乳腺癌细胞的生长，而细胞表面抗原CD36（又称血小板糖蛋白4、脂肪酸转位酶、清道夫受体B家族成员3、糖蛋白88、糖蛋白IIIb、糖蛋白IV）对癌细胞转移具有促进作用。不过，CD36对乳腺癌细胞的增殖、迁移、他莫昔芬抑制雌激素受体阳性乳腺癌细胞生长的影响尚不明确。 2018年12月21日，英国《自然》旗下《肿瘤发生》在线发表中国合肥工业大学、天津南开大学、天津中医药大学的研究报告，CD36对雌激素受体阳性乳腺癌细胞的增殖、迁移和他莫昔芬抑制生长发挥关键作用。 该研究发现乳腺癌患者的死亡率与肿瘤CD36表达水平相关，还发现雌激素受体阳性细胞（MCF-7、T-47D、ZR-75-30）与雌激素受体阴性细胞（MDA-MB-231）相比，CD36表达水平显著较高。通过CD36的小分子干扰核糖核酸，可以抑制MCF-7和MDA-MB-231细胞的生存能力和迁移能力，尤其对于MCF-7细胞。反之，CD36高表达可以促进细胞的生长和迁移。 机制分析表明，CD36可以提高细胞增殖、迁移、抗凋亡相关基因的表达水平，还可以激活雌激素受体α、受雌激素受体控制的细胞分裂周期蛋白D1以及磷酸化雌激素受体K1/2。他莫昔芬可以抑制雌激素受体α阳性而非雌激素受体α阴性细胞的CD36和磷酸化雌激素受体K1/2。反之，CD36高表达可以抑制他莫昔芬对MCF-7细胞生长的抑制作用。他莫昔芬耐药MCF-7细胞与正常MCF-7细胞相比，CD36、雌激素受体α、磷酸化雌激素受体K1/2表达水平显著较高。不过，CD36的小分子干扰核糖核酸可以恢复他莫昔芬对MCF-7耐药细胞生长的抑制能力。此外，CD36抗体可以抑制细胞生长和雌激素受体α、磷酸化雌激素受体K1/2、细胞分裂周期蛋白D1的表达。 因此，该研究结果表明，CD36通过增强乳腺癌细胞的增殖、迁移，同时减弱他莫昔芬对雌激素受体阳性细胞生长的抑制作用，可以促进乳腺癌的生长、转移、耐药，有望成为他莫昔芬耐药乳腺癌的治疗靶点。 Oncogenesis. 2018 Dec 21;7(12):98. CD36 plays a critical role in proliferation, migration and tamoxifen-inhibited growth of ER-positive breast cancer cells. Yu Liang, Hao Han, Lipei Liu, Yajun Duan, Xiaoxiao Yang, Chuanrui Ma, Yan Zhu, Jihong Han, Xiaoju Li, Yuanli Chen. Hefei University of Technology, Hefei, China; Nankai University, Tianjin, China; Tianjin University of Traditional Chinese Medicine, Tianjin, China. Tamoxifen inhibits estrogen receptor (ER)-positive breast cancer growth while CD36 potentiates cancer metastasis. The effects of CD36 on proliferation/migration of breast cancer cells and tamoxifen-inhibited ER-positive cell growth are unknown. In this study, we correlated the mortality of breast cancer patients to tumor CD36 expression levels. We also found CD36 was higher in ER-rich (MCF-7>T-47D~ZR-75-30) than ER-negative (MDA-MB-231) cells. CD36 siRNA decreased viability and migration of MCF-7 and MDA-MB-231 cells with more potent effects on MCF-7 cells. Inversely, high expressing CD36 enhanced cell growth/migration. Mechanistically, CD36 increased expression of genes responsible for cell proliferation, migration and anti-apoptosis. CD36 also activated ERα and ER-targeted genes for cell cycles, and phosphorylated ERK1/2 (p-ERK1/2). Tamoxifen inhibited CD36 and p-ERK1/2 in ERα-positive but not ERα-negative cells. Reciprocally, inhibition of MCF-7 cell growth by tamoxifen was attenuated by high expressing CD36. CD36, ERα and p-ERK1/2 expression was higher in tamoxifen-resistant MCF-7 (MCF-7/TAMR) cells than normal MCF-7 cells. However, CD36 siRNA restored the capacity of tamoxifen inhibiting MCF-7/TAMR cell growth. CD36 antibody inhibited cell growth and expression of ERα, p-ERK1/2 and CCND1. Therefore, our study unveils a pro-tumorigenic role of CD36 in breast cancer by enhancing proliferation/migration of breast cancer cells while attenuating tamoxifen-inhibited ER-positive cell growth. DOI: 10.1038/s41389-018-0107-x
|
|
|
