Abstract
BackgroundTGFβ signaling exerts context-specific effects in breast cancer (BC) pathogenesis and single nucleotide polymorphisms (SNPs) in TGFβ-signaling components play a role in the genetic control of their expression and in BC susceptibility and clinical presentation. However, studies investigating the association between the TGFβ-signaling molecules and BC prognosis rarely considered disease subtypes and SNPs. Therefore, the present study aimed to evaluate the expression of TGFβ-signaling components in BC tissue from patients with available data regarding TGFB1 and TGFBR2 SNPs and plasmatic TGFβ1 levels.MethodsImmunostaining for TGFβ1, TGFβRII and phosphorylated (p)-SMAD2/3 was investigated in primary tumor tissue from 34 patients with luminal-B-HER2+ (LB-HER2), HER2-enriched (HER2) and triple negative (TN) BC subtypes genotyped for TGFB1 (rs1800468, rs1800469, rs1800470 and rs1800471) and TGFBR2 (rs3087465) SNPs.ResultsStrong positive correlations were observed between TGFβ1, TGFβRII and p-SMAD2/3 in tumor tissue, and an inverse correlation was observed between intratumor and plasmatic TGFβ1 levels in TN BCs. In LB-HER2+ tumors, p-SMAD2/3 was associated with older age at diagnosis and inversely correlated with p53 staining and lymph-node metastasis, while tumor-size negatively correlated with TGFβ1 and TGFβRII in this BC subgroup. Also, in p53-negative BCs, tumor size and Ki67 negatively correlated with both TGFβ1, TGFβRII and p-SMAD2/3. No correlation was found between SNPs and TGFβ1-signaling components expression.ConclusionTGFβ1 canonical signaling is activated in approximately half of BCs, and correlation between TGFβ components indicate a paracrine activation, which may exert tumor suppressor effects in p53-negative or Luminal-B-HER2+ subgroups.
Highlights
Transforming growth factor beta β (TGFβ) signaling exerts context-specific effects in breast cancer (BC) pathogenesis and single nucleotide polymorphisms (SNPs) in TGFβ-signaling components play a role in the genetic control of their expression and in BC susceptibility and clinical presentation
TGFβ1 and TGFβRII immunostainings had bimodal distributions that were consistent among different subtypes, with the average value dividing the sample into low and high expression groups (Fig. 2a and b)
For p-SMAD2/3, otherwise, data distribution assumed a continuous behavior for LB and triple negative (TN) subgroups, but was bimodal for HER2 BCs (Fig. 2c)
Summary
TGFβ signaling exerts context-specific effects in breast cancer (BC) pathogenesis and single nucleotide polymorphisms (SNPs) in TGFβ-signaling components play a role in the genetic control of their expression and in BC susceptibility and clinical presentation. Studies investigating the association between the TGFβ-signaling molecules and BC prognosis rarely considered disease subtypes and SNPs. the present study aimed to evaluate the expression of TGFβ-signaling components in BC tissue from patients with available data regarding TGFB1 and TGFBR2 SNPs and plasmatic TGFβ1 levels. Intratumor growth factors and cytokines seems to play a special role controlling both tumor-cell-intrinsic programs, such as apoptosis, survival, proliferation and differentiation, as well as stromal-related processes, such as angiogenesis, extracellular matrix remodeling and anti-tumor immune responses, which together can facilitate BC evolution and metastasis (Tata et al 2019). All the three isoforms are secreted as an inactive large latent complex which remains attached to the extracellular matrix until they are activated by diverse stimuli such as acidification, oxidative stress or through the activity of metalloproteinases (Kubiczkova et al 2012)
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