Abstract
Purpose
Despite the documented dual role of TGFβ1 in breast cancer (BC) pathogenesis, the subtype-specific influences of its polymorphisms remain undocumented. The present study investigated the effects of the TGFB1 promoter region (rs1800468 or G-800A and rs1800469 or C-509T) and signal peptide (rs1800470 or C29T and rs1800471 or G74C) single nucleotide polymorphisms (SNPs) and their haplotype structures on the susceptibility and clinicopathological presentation of BC subtypes.
Methods
TGFB1 genotypes were assessed by PCR-RFLP and haplotype structures were inferred for 323 BC patients and 405 neoplasia-free women, and case–control analyses were performed by logistic regression adjusted by age. Clinicopathological parameters (age at diagnosis, tumor size, histopathological grade, lymph node metastasis, proliferation index and disease stage) were tested for correlation with TGFB1 variants. All statistical analyses were two-tailed with an alpha level of 0.05.
Results
Variants related to increased TGFβ1 production (C-509T SNP and GTCG haplotype) were associated with increased susceptibility to HER2+ tumors and correlated with worse prognostic parameters in HER2+ and triple-negative (TN) BCs, but correlated negatively to Ki67 in ER/PR+HER2− tumors. Conversely, low TGFβ1 production variants (C29T SNP and GCTG haplotype) were protective against HER2+ tumors and correlated negatively with prognostic parameters in HER2+ and TN BCs, while indicating higher proliferation rates in ER/PR+HER2− tumors. Furthermore, the GCCG haplotype was associated with decreased susceptibility to ER/PR+HER2− tumors, but correlated positively with Ki67 in this subgroup.
Conclusion
The present study indicates that TGFB1 variants have subtype-specific roles in BC and may switch from tumor suppressor to promoter during tumor development, consistent with TGFβ1 dual role in BC pathogenesis.
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Acknowledgements
The authors acknowledge all the volunteer donors involved in this study and the Clinical Hospital (HC-UEL) and Londrina Cancer Hospital (HCL) staff for supporting during sample collection.
Funding
This study was supported by the Brazilian National Council for Scientific and Technological Development (CNPq, process 303186/2015-1), Fundação Araucária (1027/2013) and by the Londrina State University Postgraduate Coordination (PROPPG-UEL).
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Informed consent was obtained from all individual participants included in the study.
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Vitiello, G.A.F., Guembarovski, R.L., Hirata, B.K.B. et al. Transforming growth factor beta 1 (TGFβ1) polymorphisms and haplotype structures have dual roles in breast cancer pathogenesis. J Cancer Res Clin Oncol 144, 645–655 (2018). https://doi.org/10.1007/s00432-018-2585-9
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DOI: https://doi.org/10.1007/s00432-018-2585-9