title: Proliferative genes dominate malignancy-risk gene signature in histologically-normal breast tissue.
abstract: Historical data have indicated the potential for the histologically-normal breast to harbor pre-malignant changes at the molecular level. We postulated that a histologically-normal tissue with "tumor-like" gene expression pattern might harbor substantial risk for future cancer development. Genes associated with these high-risk tissues were considered to be "malignancy-risk genes". From a total of 90 breast cancer patients, we collected a set of 143 histologically-normal breast tissues derived from patients harboring breast cancer who underwent curative mastectomy, as well as a set of 42 invasive ductal carcinomas (IDC) of various histologic grades. All samples were assessed for global gene expression differences using microarray analysis. For the purpose of this study we defined normal breast tissue to include histologically normal and benign lesions. Here we report the discovery of a "malignancy-risk" gene signature that may portend risk of breast cancer development in benign, but molecularly-abnormal, breast tissue. Pathway analysis showed that the malignancy-risk signature had a dramatic enrichment for genes with proliferative function, but appears to be independent of ER, PR, and HER2 status. The signature was validated by RT-PCR, with a high correlation (Pearson correlation = 0.95 with P < 0.0001) with microarray data. These results suggest a predictive role for the malignancy-risk signature in normal breast tissue. Proliferative biology dominates the earliest stages of tumor development.
authors.affiliation: Biostatistics Department, Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
authors.forename: Dung-Tsa
authors.initials: DT
authors.lastname: Chen
authors.forename: Aejaz
authors.initials: A
authors.lastname: Nasir
authors.forename: Aedin
authors.initials: A
authors.lastname: Culhane
authors.forename: Chinnambally
authors.initials: C
authors.lastname: Venkataramu
authors.forename: William
authors.initials: W
authors.lastname: Fulp
authors.forename: Renee
authors.initials: R
authors.lastname: Rubio
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Deepak
authors.initials: D
authors.lastname: Agrawal
authors.forename: Susan M
authors.initials: SM
authors.lastname: McCarthy
authors.forename: Mike
authors.initials: M
authors.lastname: Gruidl
authors.forename: Gregory
authors.initials: G
authors.lastname: Bloom
authors.forename: Tove
authors.initials: T
authors.lastname: Anderson
authors.forename: Joe
authors.initials: J
authors.lastname: White
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.forename: Timothy
authors.initials: T
authors.lastname: Yeatman
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D018270:Carcinoma, Ductal, Breast / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D016022:Case-Control Studies; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D008408:Mastectomy; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D025341:Principal Component Analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human