title: ErbB2, FoxM1 and 14-3-3ζ prime breast cancer cells for invasion in response to ionizing radiation.
abstract: ErbB2 is frequently highly expressed in premalignant breast cancers, including ductal carcinoma in situ (DCIS); however, little is known about the signals or pathways it contributes to progression into the invasive/malignant state. Radiotherapy is often used to treat early premalignant lesions regardless of ErbB2 status. Here, we show that clinically relevant doses of ionizing radiation (IR)-induce cellular invasion of ErbB2-expressing breast cancer cells, as well as MCF10A cells overexpressing ErbB2. ErbB2-negative breast cancer cells, such as MCF7 and T47D, do not invade following treatment with IR nor do MCF10A cells overexpressing epidermal growth factor receptor. ErbB2 becomes phosphorylated at tyrosine 877 in a dose- and time- dependent manner following exposure to X-rays, and activates downstream signaling cascades including PI3K/Akt. Inhibition of these pathways, as well as inhibition of reactive oxygen species (ROS) with antioxidants, prevents IR-induced invasion. Activation of ErbB2-dependent signaling results in upregulation of the forkhead family transcription factor, FoxM1, and its transcriptional targets, including matrix metalloproteinase 2 (MMP2). Inhibition of FoxM1 by RNA interference prevented induction of invasion by IR, and overexpression of FoxM1 in MCF10A cells was sufficient to promote IR-induced invasion. Moreover, we found that 14-3-3ζ is also upregulated by IR in cancer cells in a ROS-dependent manner, is required for IR-induced invasion in ErbB2-positive breast cancer cells and together with FoxM1 is sufficient for invasion in ErbB2-negative breast cancer cells. Thus, our data show that IR-mediated activation of ErbB2 and induction of 14-3-3ζ collaborate to regulate FoxM1 and promote invasion of breast cancer cells and furthermore, may serve as therapeutic targets to enhance radiosensitivity of breast cancers.
authors: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors: D M
authors: DM
authors: Kambach
authors: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors: V L
authors: VL
authors: Sodi
authors: School of Biomedical Engineering, Drexel University, Philadelphia, PA, USA.
authors: P I
authors: PI
authors: Lelkes
authors: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors: J
authors: J
authors: Azizkhan-Clifford
authors: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors: M J
authors: MJ
authors: Reginato
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000473:pathology* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects
chemical_list: D048948:14-3-3 Proteins; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D020778:Matrix Metalloproteinase 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; C107585:FOXM1 protein, human; C572235:YWHAZ protein, human; C508053:ERBB2 protein, human; C522361:MMP2 protein, human