Association of single nucleotide polymorphisms in FGF-RAS/MAP signalling cascade with breast cancer susceptibility

Abstract

Abstract. The fibroblast growth factor receptors (FGFRs) and Ras/mitogen activated protein (RAS/ MAP) signalling cascades are the main molecular pathways involved in breast carcinogenesis. This study aims to determine the association between FGF10 (rs4415084 C>T), FGFR2 (rs2981582 C>T) and MAP3K1 (rs889312 A>C) gene polymorphisms and breast cancer, to analyse the discriminative ability of each SNP and to test the accuracy of the predictive breast cancer risk model which includes all SNPs. We conducted a case-control study of 170 women (57.06 ± 11.60 years) with histologically confirmed breast cancer and 146 controls (50.24 ± 10.69 years). High resolution melting (HRM) method with Sanger sequencing validation was used in analyses. We have revealed significant association of FGFR2 and MAP3K1 polymorphisms with breast cancer. The odds ratio of FGFR2 T allele was 1.897 (95% CI 1.231-2.936, p = 0.004) and MAP3K1 C allele 1.804 (95% CI 1.151-2.845, p = 0.012). FGFR2 polymorphism achieved the best discriminative ability (41.95%). The Random Forest algorithm selected FGFR2, MAP3K1 and age as important breast cancer predictors. The accuracy of this prediction model approached moderate accuracy (70%), with 35.9% sensitivity and 88.6% specificity.

Fibroblast growth factor receptor signalling dysregulation and targeting in breast cancer

“…From a mechanistic point of view, it has been suggested that histone acetylation modulates access to selected polymorphic sites within intron 2, thus regulating downstream splicing sites, which generates FGFR2c isoforms [ 207 ]. As there is also evidence for gene polymorphism of the FGFR2b ligand FGF10 [ 208 ], it would be worth exploring in detail the consequences of these nuclear events on the expression of different receptor isoforms and on signalling activation and specificity in both pre-clinical models and patient-derived samples. Interestingly, BRCA-1- and ER-double-positive breast cancers showed not only increased expression of FGFR2 [ 209 ] but also the presence of the SNP rs2981582 [ 210 ], which is associated with high risk of breast cancer [ 211 ].…”

LncRNA-SNPs in a Brazilian Breast Cancer Cohort: A Case-Control Study

“…Both are related to an increased risk of BC development in the analyzed population. The rs4415084 has already been highlighted as relevant in the development of BC in Caucasian Slavic [24], Chinese [25,26], and European populations [27]. Additionally, lncRNA-SNP rs4415084 was significantly associated with progesterone receptor status considering the recessive and over-dominant models (Table 8), the presence of the C allele (CC/CT) being associated with the positivity of the progesterone receptor.…”

The interplay among MAP3K1 and SOX2 regulated metastasis by MAPK signaling pathway through interaction with KLF4 in triple-negative breast cancer

“…In the Ras-Raf-MEK-ERKMAPK cascade, Ras binds to and promote activation of Raf [7,31]. Over-expression of Ras activates MAPKs, is fully capable to induce metastatic mammary tumors in mice [7,10,22] and also help induce human mammary epithelial cells to form ductal carcinoma in situ, followed by development of invasive ductal carcinoma in mouse mammary glands [32,33] (our mice model is a ductal carcinoma model [17]). ERK can trigger tumor suppressor pathways such as cellular senescence, apoptosis and differentiation.…”

“…MAP3K1 may be a downstream effector of Ras signaling. The current thinking proposes that both Ras and Raf oncogenes promote human cancers by activating the ERK kinases [22,23]. ERK can activate KLF4 [10,11].…”