Glauco Akelinghton Freire Vitiello1, Roberta Losi Guembarovski2, Bruna Karina Banin Hirata1, Marla Karine Amarante1, Carlos Eduardo Coral de Oliveira1, Karen Brajão de Oliveira1, Guilherme Cesar Martelossi Cebinelli1, Alda Losi Guembarovski3, Clodoaldo Zago Campos4, Maria Angelica Ehara Watanabe5. 1. Laboratory of studies and applications of DNA polymorphisms and Immunology, Department of Pathological Sciences, Biological Sciences Center, Londrina State University, PR445 (Celso Garcia Cid highway), Km 380, Londrina, PR, 86057-970, Brazil. 2. Department of General Biology, Londrina State University, Londrina, Parana, Brazil. 3. Department of Pathology, Clinical and Toxicological Analysis, Londrina State University, Londrina, Parana, Brazil. 4. Department of Clinical Research, Londrina Cancer Hospital, Londrina, Parana, Brazil. 5. Laboratory of studies and applications of DNA polymorphisms and Immunology, Department of Pathological Sciences, Biological Sciences Center, Londrina State University, PR445 (Celso Garcia Cid highway), Km 380, Londrina, PR, 86057-970, Brazil. maewatuel@gmail.com.
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.
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.
Entities:
Keywords:
Breast cancer; Haplotypes; Polymorphisms; Prognosis; Subtypes; TGFβ1
Authors: Olga V Zhukova; Evgenia V Arkhipova; Tatiana F Kovaleva; Daria A Zykova; Natalya A Dubovskaya Journal: Molecules Date: 2022-07-18 Impact factor: 4.927