title: Paired-like Homeodomain Transcription factor 2 expression by breast cancer bone marrow disseminated tumor cells is associated with early recurrent disease development.
abstract: The presence of disseminated tumor cells (DTCs) in the bone marrow (BM) of breast cancer patients is prognostic for early relapse. In the present study, we analyzed the gene expression profiles from BM cells of breast cancer patients to identify molecular signatures associated with DTCs and their relevance to metastatic outcome. We analyzed BM from 30 patients with stage II/III breast cancer by gene expression profiling and correlated expression with metastatic disease development. A candidate gene, PITX2, was analyzed for expression and phenotype in breast cancer cell lines. PITX2 was knocked down in the MDAMB231 cell lines for gene expression analysis and cell invasiveness. Expression of various signaling pathway molecules was confirmed by RT-PCR. We found that the expression of Paired-like Homeobox Transcription factor-2 (PITX2) is absent in the BM of normal healthy volunteers and, when detected in the BM of breast cancer patients, is significantly correlated with early metastatic disease development (p = 0.0062). Suppression of PITX2 expression significantly reduced invasiveness in MDAMB231 cells. Three genes-NKD1, LEF1, and DKK4-were significantly downregulated in response to PITX2 suppression. Expression of PITX2 in BM of early-stage breast cancer patients is associated with risk for early disease recurrence. Furthermore, PITX2 likely plays a role in the metastatic process through its effect on the expression of genes associated with the Wnt/beta-Catenin signaling pathway.
authors.affiliation: Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Sreeraj G
authors.initials: SG
authors.lastname: Pillai
authors.affiliation: Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA.|Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Nupur
authors.initials: N
authors.lastname: Dasgupta
authors.affiliation: Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Chidananda M
authors.initials: CM
authors.lastname: Siddappa
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.|Siteman Cancer Center, Department of Surgery, Biostatistics Shared Resource, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Watson
authors.affiliation: Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Fleming
authors.affiliation: Siteman Cancer Center, Department of Surgery, Biostatistics Shared Resource, Washington University School of Medicine, St. Louis, MO, USA.|Siteman Cancer Center at the Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Trinkaus
authors.affiliation: Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA. aftr@wustl.edu.|Siteman Cancer Center at the Washington University School of Medicine, St. Louis, MO, USA. aftr@wustl.edu.|John Cochran Veterans Administration Hospital, St. Louis, MO, USA. aftr@wustl.edu.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Aft
mesh_terms: D014408:Biomarkers, Tumor; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001859:Bone Neoplasms / Q000235:genetics* / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009687:Nuclear Proteins; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051879:Twist-Related Protein 1; D000097577:Homeobox Protein PITX2
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D000097577:Homeobox Protein PITX2; C103173:TWIST1 protein, human
keywords: Breast cancer; Disseminated tumor cells; Gene expression; Invasiveness; Metastasis; PITX2; Wnt signaling