title: FoxM1 promotes breast tumorigenesis by activating PDGF-A and forming a positive feedback loop with the PDGF/AKT signaling pathway.
abstract: The autocrine platelet-derived growth factor (PDGF)/PDGF receptor (PDGFR) signaling pathway promotes breast cancer tumorigenesis, but the mechanisms for its dysregulation in breast cancer are largely unknown. In the study, we identified PDGF-A as a novel transcriptional target of FoxM1. FoxM1 directly binds to two sites in the promoter of PDGF-A and activates its transcription. Mutation of these FoxM1-binding sites diminished PDGF-A promoter activity. Increased FoxM1 resulted in the upregulation of PDGF-A, which led to activation of the AKT pathway and increased breast cancer cell proliferation and tumorigenesis, whereas knockdown of FoxM1 does the opposite. Blocking AKT activation with a phosphoinositide 3-kinase/AKT inhibitor decreased FoxM1-induced cell proliferation. Moreover, PDGF/AKT pathway upregulates the expression of FoxM1 in breast cancer cells. Knockdown of PDGF-A or blockade of AKT activation inhibited the expression of FoxM1 in breast cancer cells. Furthermore, expression of FoxM1 significantly correlated with the expression of PDGF-A and the activated AKT signaling pathway in human breast cancer specimens. Our study demonstrates a novel positive regulatory feedback loop between FoxM1 and the PDGF/AKT signaling pathway; this loop contributes to breast cancer cell growth and tumorigenesis.
authors: Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Medical Oncology, Changzheng Hospital, Shanghai, People's Republic of China.
authors: Guanzhen
authors: G
authors: Yu
authors: Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Aidong
authors: A
authors: Zhou
authors: Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Jianfei
authors: J
authors: Xue
authors: Departments of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Chen
authors: C
authors: Huang
authors: Department of Medical Oncology, Changzheng Hospital, Shanghai, People's Republic of China.
authors: Xia
authors: X
authors: Zhang
authors: Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Shin-Hyuk
authors: SH
authors: Kang
authors: Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Wen-Tai
authors: WT
authors: Chiu
authors: Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Christina
authors: C
authors: Tan
authors: Departments of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors: Keping
authors: K
authors: Xie
authors: Department of Medical Oncology, Changzheng Hospital, Shanghai, People's Republic of China.
authors: Jiejun
authors: J
authors: Wang
authors: Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors: Suyun
authors: S
authors: Huang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019898:Autocrine Communication; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D025461:Feedback, Physiological; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; C075278:platelet-derived growth factor A; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; FoxM1; PDGF-A; breast cancer; tumorigenesis