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.