Expression of TGF-beta signaling factors in invasive breast cancers: relationships with age at diagnosis and tumor characteristics.
The transforming growth factor beta (TGF-beta) pathway can play either a tumor-suppressing or a tumor-promoting role in human breast carcinogenesis. In order to determine whether expression of TGF-beta signaling factors varies by age at onset and breast tumor characteristics that have prognostic significance, we undertook a study of 623 women with invasive breast carcinoma enrolled in a population-based case-control study conducted in Poland from 2000 to 2003. TGF-beta signaling factors were analyzed by immunohistochemistry in tumor tissue microarrays. We found that most tumors expressed extracellular-TGF-beta1 (78%), TGF-beta2 (91%), TGF-beta3 (93%), TGF-betaR2 (72%), and phospho-SMAD2 (61%), whereas intracellular-TGF-beta1 was expressed in 32% of tumors. Expression of TGF-beta ligands (beta1, beta2, and beta3) was associated with prognostically favorable pathological features including small size, and low grade, and these associations were similar for ER-positive and negative tumors. On the contrary, expression of the receptor TGF-betaR2 was primarily associated with small tumor size among ER-negative tumors, while expression of the transcription factor phospho-SMAD2 was associated with positive nodal status among ER-negative tumors. The greater frequency of expression of phospho-SMAD2 in cancers associated with lymph node metastases is consistent with a pro-progression role for TGF-beta. In addition, expression of extracellular-TGF-beta1 (P = 0.005), TGF-betaR2 (P = 8.2E-11), and phospho-SMAD2 (P = 1.3E-8) was strongly associated with earlier age at onset, independent of ER status. Our data provide evidence that TGF-beta signaling patterns vary by age and pathologic features of prognostic significance including ER expression. These results warrant analysis in studies of clinical outcomes accounting for age, ER status and treatment.
Figueroa
Jonine D
JD
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. figueroaj@mail.nih.gov
Flanders
Kathleen C
KC
Garcia-Closas
Montserrat
M
Anderson
William F
WF
Yang
Xiaohong R
XR
Matsuno
Rayna K
RK
Duggan
Máire A
MA
Pfeiffer
Ruth M
RM
Ooshima
Akira
A
Cornelison
Robert
R
Gierach
Gretchen L
GL
Brinton
Louise A
LA
Lissowska
Jolanta
J
Peplonska
Beata
B
Wakefield
Lalage M
LM
Sherman
Mark E
ME
D000328:Adult; D017677:Age Distribution; D017668:Age of Onset; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D011044:Poland / Q000453:epidemiology; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D011960:Receptors, Estrogen / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II