Cellular transformation of human mammary epithelial cells by SATB2.
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.
Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 66128, United States.
Wei
W
Yu
Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 66128, United States.
Yiming
Y
Ma
Stanley S. Scott Cancer Center, Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, United States.
Augusto C
AC
Ochoa
Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 66128, United States; Department of Pathology, University of Missouri-School of Medicine, Kansas City, MO 64108, United States.
Sharmila
S
Shankar
Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 66128, United States; Department of Pharmacology and Toxicology, University of Missouri, Kansas City, MO 64108, United States. Electronic address: rsrivastava.lab@gmail.com.
Rakesh K
RK
Srivastava
D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D016086:Lentivirus / Q000235:genetics; D042361:Mammary Glands, Human / Q000166:cytology*; D036961:Matrix Attachment Region Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D036961:Matrix Attachment Region Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C521297:SATB2 protein, human; D014157:Transcription Factors; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human