Gene expression abnormalities in histologically normal breast epithelium of breast cancer patients.
Normal-appearing epithelium of cancer patients can harbor occult genetic abnormalities. Data comprehensively comparing gene expression between histologically normal breast epithelium of breast cancer patients and cancer-free controls are limited. The present study compares global gene expression between these groups. We performed microarrays using RNA from microdissected histologically normal terminal ductal-lobular units (TDLU) from 2 groups: (i) cancer normal (CN) (TDLUs adjacent to untreated ER+ breast cancers (n = 14)) and (ii) reduction mammoplasty (RM) (TDLUs of age-matched women without breast disease (n = 15)). Cyber-T identified differentially expressed genes. Quantitative RT-PCR (qRT-PCR), immunohistochemistry (IHC), and comparison to independent microarray data including 6 carcinomas in situ (CIS), validated the results. Gene ontology (GO), UniProt and published literature evaluated gene function. About 127 probesets, corresponding to 105 genes, were differentially expressed between CN and RM (p < 0.0009, corresponding to FDR <0.10). 104/127 (82%) probesets were also differentially expressed between CIS and RM, nearly always (102/104 (98%)) in the same direction as in CN vs. RM. Two-thirds of the 105 genes were implicated previously in carcinogenesis. Overrepresented functional groups included transcription, G-protein coupled and chemokine receptor activity, the MAPK cascade and immediate early genes. Most genes in these categories were under-expressed in CN vs. RM. We conclude that global gene expression abnormalities exist in normal epithelium of breast cancer patients and are also present in early cancers. Thus, cancer-related pathways may be perturbed in normal epithelium. These abnormalities could be markers of disease risk, occult disease, or the tissue's response to an existing tumor.
Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, MA 02118, USA.
Anusri
A
Tripathi
Chialin
C
King
Antonio
A
de la Morenas
Victoria Kristina
VK
Perry
Bohdana
B
Burke
Gregory A
GA
Antoine
Erwin F
EF
Hirsch
Maureen
M
Kavanah
Jane
J
Mendez
Michael
M
Stone
Norman P
NP
Gerry
Marc E
ME
Lenburg
Carol L
CL
Rosenberg
D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis; D001940:Breast / Q000033:anatomy & histology / Q000737:chemistry*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000032:analysis*; D004848:Epithelium / Q000737:chemistry* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D016462:Mammaplasty; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000032:analysis*
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D014157:Transcription Factors