A Transforming Growth Factor beta 1 Signal Peptide Variant Increases Secretion in Vitro and Is Associated with Increased Incidence of Invasive Breast Cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2003-05, Vol.63 (10), p.2610-2615
• Main Authors: Dunning, A M, Ellis, P D, McBride, S, Kirschenlohr, H L, Healey, C S, Kemp, PR, Luben, R N, Chang-Claude, J, Mannermaa, A, Kataja, V, Pharoah, PDP, Easton, D F, Ponder, BAJ, Metcalfe, J C
• Format: Article
• Language: English
• ISSN: 0008-5472

There is evidence that transforming growth factor (TGF) beta acts as a suppressor of tumor initiation but also as a promoter of tumor progression when the antiproliferative effect of the TGF beta signaling pathway has been overridden by other oncogenic mutations. Several somatic mutations that disrupt the TGF beta -SMAD signaling pathway have been reported in human breast tumors. We have examined the association between single nucleotide polymorphisms (SNPs) in the TGF beta 1 gene and the incidence of invasive breast cancer in three case-control series, with a maximum of 3987 patients and 3867 controls, median age similar to 50 years, and range 22-92 years. The promoter SNP, C-509T, and the T + 29C signal-peptide SNP (encoding Leu10Pro) are in strong linkage disequilibrium. They are both significantly associated with increased incidence of invasive breast cancer in a recessive manner [odds ratios: (TT versus C-carrier), 1.25; 95% confidence intervals 1.06-1.48; P = 0.009 and (ProPro versus Leu-carrier), 1.21; 95% confidence intervals 1.05-1.37; P = 0.01]. The G-800A SNP was not significantly associated with incidence of breast cancer. The C-509T SNP is not contained within a known consensus sequence for a promoter regulatory element and therefore unlikely to affect TGF beta 1 expression, whereas the Leu10Pro signal peptide substitution potentially affects TGF beta 1 secretion. Transfections of HeLa cells with constructs encoding either the Pro or Leu forms of TGF beta 1 and driven by the cytomegalovirus promoter indicate that the signal peptide with Pro at residue 10 causes a 2.8-fold increase in secretion compared with the Leu form. These data indicate that the allele encoding Pro10 is associated with increased rates of TGF beta 1 secretion and with increased incidence of invasive breast cancer for the population samples described. It is estimated that 3% of all breast cancer cases may be attributable to Pro10 homozygosity.