Yu Wei, Ma Yiming, Ochoa Augusto C, Shankar Sharmila, Srivastava Rakesh K
Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 66128, United States.
Stanley S. Scott Cancer Center, Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, United States.
Stem Cell Res. 2017 Mar;19:139-147. doi: 10.1016/j.scr.2017.01.011. Epub 2017 Feb 1.
Breast tumors are heterogeneous and carry a small population of progenitor cells that can produce various subtypes of breast cancer. SATB2 (special AT-rich binding protein-2) is a newly identified transcription factor and epigenetic regulator. It is highly expressed in embryonic stem cells, but not in adult tissues, and regulates pluripotency-maintaining factors. However, the molecular mechanisms by which SATB2 induces transformation of human mammary epithelial cells (HMECs) leading to malignant phenotype are unknown. The main goal of this paper is to examine the molecular mechanisms by which SATB2 induces cellular transformation of HMECs into cells that are capable of self-renewal. SATB2-transformed HMECs gain the phenotype of breast progenitor cells by expressing markers of stem cells, pluripotency-maintaining factor, and epithelial to mesenchymal transition. SATB2 is highly expressed in human breast cancer cell lines, primary mammary tissues and cancer stem cells (CSCs), but not in HMECs and normal breast tissues. Chromatin Immunoprecipitation assays demonstrate that SATB2 can directly bind to promoters of Bcl-2, c-Myc, Nanog, Klf4, and XIAP, suggesting a role of SATB2 in regulation of pluripotency, cell survival and proliferation. Furthermore, inhibition of SATB2 by shRNA in breast cancer cell lines and CSCs attenuates cell proliferation and EMT phenotype. Our results suggest that SATB2 induces dedifferentiation/transformation of mature HMECs into progenitor-like cells.
乳腺肿瘤具有异质性，含有一小部分祖细胞，这些祖细胞可产生各种亚型的乳腺癌。SATB2（富含AT的特殊结合蛋白2）是一种新发现的转录因子和表观遗传调节因子。它在胚胎干细胞中高度表达，但在成年组织中不表达，并调节多能性维持因子。然而，SATB2诱导人乳腺上皮细胞（HMECs）转化导致恶性表型的分子机制尚不清楚。本文的主要目的是研究SATB2诱导HMECs细胞转化为具有自我更新能力的细胞的分子机制。SATB2转化的HMECs通过表达干细胞标志物、多能性维持因子和上皮-间质转化标志物，获得了乳腺祖细胞的表型。SATB2在人乳腺癌细胞系、原发性乳腺组织和癌干细胞（CSCs）中高度表达，但在HMECs和正常乳腺组织中不表达。染色质免疫沉淀分析表明，SATB2可直接结合Bcl-2、c-Myc、Nanog、Klf4和XIAP的启动子，提示SATB2在多能性、细胞存活和增殖调节中发挥作用。此外，在乳腺癌细胞系和CSCs中用shRNA抑制SATB2可减弱细胞增殖和EMT表型。我们的结果表明，SATB2诱导成熟的HMECs去分化/转化为祖细胞样细胞。
