Decreased TGFbeta signaling and increased COX2 expression in high risk women with increased mammographic breast density.
High mammographic density is associated with a increased risk of breast cancer. We hypothesized that specific pathways exist that are associated with increased mammographic density, and may therefore be used to identify potential targets for chemoprevention. Histologically confirmed normal breast tissue was collected from women undergoing breast surgery who had available demographic data and mammograms for review. Women with low versus high mammographic breast density were compared. Differentially expressed genes using Affymetrix HG U133Plus2 chips were identified in dense versus non-dense tissue. Immunohistochemical analysis (IHC) of estrogen receptor, progesterone receptor, Ki67, and COX2 expression was performed. About 66 women were identified, 28 (42%) had high, and 38 (58%) had low mammographic density. About 73 genes had differential expression between normal breast tissue with high and low mammographic density (P < 0.001, fold change > or = 1.5 with a low false discovery rate (<10%). Network and canonical pathway analysis indicated decreased TGFbeta signaling (TGFBR2, SOS, SMAD3, CD44 and TNFRSF11B) in dense breast tissue relative to non-dense breast. By IHC, only COX2 expression in the stroma was statistically significant on multivariate analysis. TGFbeta ligands are currently the only growth factors known to prevent mammary epithelial cell proliferation. TGFbeta signaling has been reported to be inhibited by COX-2, and these molecules are highly differentially expressed in individuals at high risk of developing breast cancer. These results strongly suggest that COX2 inhibition should be investigated for breast cancer prevention despite possible increase in cardiovascular risk.
Yang
Wei Tse
WT
University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. wyang@di.mdacc.tmc.edu
Lewis
Michael T
MT
Hess
Kenneth
K
Wong
Helen
H
Tsimelzon
Anna
A
Karadag
Nese
N
Cairo
Michelina
M
Wei
Caimaio
C
Meric-Bernstam
Funda
F
Brown
Powel
P
Arun
Banu
B
Hortobagyi
Gabriel N
GN
Sahin
Aysegul
A
Chang
Jenny C
JC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D051546:Cyclooxygenase 2 / Q000032:analysis* / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D016015:Logistic Models; D008327:Mammography; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000000981:diagnostic imaging* / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000032:analysis* / Q000235:genetics; D015854:Up-Regulation
D016588:Anticarcinogenic Agents; D052246:Cyclooxygenase 2 Inhibitors; D008024:Ligands; D016212:Transforming Growth Factor beta; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human