title: Radiation promotes malignant phenotypes through SRC in breast cancer cells.
abstract: Despite the fact that ionizing radiation (IR) is widely used as a standard treatment for breast cancer, much evidence suggests that IR paradoxically promotes cancer malignancy. However, the molecular mechanisms underlying radiation-induced cancer progression remain obscure. Here, we report that irradiation activates SRC signaling among SRC family kinase proteins, thereby promoting malignant phenotypes such as invasiveness, expansion of the cancer stem-like cell population, and resistance to anticancer agents in breast cancer cells. Importantly, radiation-activated SRC induced SLUG expression and caused epithelial-mesenchymal cell transition through phosphatidylinositol 3-kinase/protein kinase B and p38 MAPK signaling. In agreement, either inhibition of SRC or downstream signaling of p38 MAPK or protein kinase B effectively attenuated radiation-induced epithelial-mesenchymal cell transition along with an increase in the cancer stem-like cell population. In addition, downregulation of SRC also abolished radiation-acquired resistance of breast cancer cells to anticancer agents such as cisplatin, etoposide, paclitaxel, and IR. Taken together, our findings suggest that combining radiotherapy with targeting of SRC might attenuate the harmful effects of radiation and enhance the efficacy of breast cancer treatment.
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
authors.forename: Rae-Kwon
authors.initials: RK
authors.lastname: Kim
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Cui
authors.forename: Ki-Chun
authors.initials: KC
authors.lastname: Yoo
authors.forename: In-Gyu
authors.initials: IG
authors.lastname: Kim
authors.forename: Minyoung
authors.initials: M
authors.lastname: Lee
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.forename: Yongjoon
authors.initials: Y
authors.lastname: Suh
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D001943:Breast Neoplasms; D002465:Cell Movement / Q000528:radiation effects; D019008:Drug Resistance, Neoplasm / Q000528:radiation effects; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition / Q000528:radiation effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases
keywords: Cancer stem cells; SRC; epithelial-mesenchymal cell transition; ionizing radiation; resistance to anticancer agents