Immunohistochemical analysis of phosphorylated mammalian target of rapamycin and its downstream signaling components in invasive breast cancer.

The present study aimed to investigate whether the mammalian target of rapamycin (mTOR) signaling pathway is activated in invasive breast cancer. The expression levels of phosphorylated (p)­mTOR at ser2448 were detected, as well as the expression levels of its downstream signaling molecules: Eukaryotic translation initiation factor 4E­binding protein 1 (4E­BP1), and p70 ribosomal protein S6 kinase 1 (S6K1). The correlation between p­mTOR, p­4E­BP1, p­S6K1, and the clinicopathological parameters of breast cancer were also determined. p­mTOR, p­4E­BP1 and p­S6K1 expression was detected in 285 breast cancer tumor samples and adjacent normal tissue samples using immunohistochemistry. The expression levels and the location of the proteins were analyzed and compared in the various tissue samples. Multivariate Cox regression was used to analyze the clinicopathological factors and prognosis associated with the tissue samples. The disease­free survival rate was examined using survival analyses and Log­rank tests. The results of the present study indicated that the expression levels of p­mTOR, p­4E­BP1, and p­S6K1 were significantly higher in breast cancer tissue, as compared with normal tissue (P<0.01). p­mTOR was predominantly expressed in the cytoplasm, whereas p­4E­BP1 and p­S6K1 were predominantly co­expressed in the cytoplasm and the nucleus. In addition, p­4E­BP1 and p­S6K1 were more likely to be expressed in the cytoplasm in breast cancer tissue samples, as compared with normal tissue samples (P<0.001). Positive p­mTOR was not significantly correlated with positive p­4E­BP1 and p­S6K1 expression. The survival analyses of the patients with positive p­mTOR, p­4E­BP1, and p­S6K1 tissue samples were not significantly different from those of the patients with negative tissue samples (P>0.05). Thus suggesting that these markers are not adequate risk factors for disease free survival (P>0.05). In conclusion, the results of the present study suggested that p­mTOR, p­4E­BP1, and p­S6K1 are activated in invasive breast cancer. In addition, the exclusive expression of p­4E­BP1 and p­S6K1 in the cytoplasm may be characteristic of progressive breast cancer. However, p­mTOR, p­4E­BP1, and p­S6K1 are not prognostic factors for breast cancer.

[Association between single nucleotide polymorphisms of BARD 1 gene and susceptibility of early-onset breast cancer in Uygur women in Xinjiang].

OBJECTIVE: To investigate the association between single nucleotide polymorphisms (SNPs) of BARD1 gene and susceptibility of early-onset breast cancer in Uygur women in Xinjiang. METHODS: A case-control study was designed to explore the genotypes of Pro24Ser (C/T), Arg378Ser (G/C) and Val507Met (G/A) of BARD1 gene, detected by PCR-restriction fragment length polymorphism (PCR-RFLP) assay, in 144 early-onset breast cancer cases of Uygur women (≤ 40 years) and 136 cancer-free controls matched by age and ethnicity. The association between SNPs of BARD1 gene and risk of early-onset breast cancer in Uygur women was analyzed by unconditional logistic regression model. RESULTS: Early age at menarche, late age at first pregnancy, and positive family history of cancer may be important risk factors of early-onset breast cancer in Uygur women in Xinjiang. The frequencies of genotypes of Pro24Ser (C/T), Arg378Ser (G/C) and Val507Met (G/A) of BARD1 gene showed significant differences between the cancer cases and cancer-free controls (P < 0.05). Compared with wild-type genotype Pro24Ser CC, it showed a lower incidence of early-onset breast cancer in Uygur women with variant genotypes of Pro24Ser TT (OR = 0.117, 95%CI = 0.058 - 0.236), and dominance-genotype CT+TT (OR = 0.279, 95%CI = 0.157 - 0.494), or Arg378Ser CC (OR = 0.348, 95%CI = 0.145 - 0.834) and Val507Met AA(OR = 0.359, 95%CI = 0.167 - 0.774). Furthermore, SNPS in three polymorphisms would have synergistic effects on the risk of breast cancer. In addition, the SNP-SNP interactions of dominance-genotypes (CT+TT, GC+CC and GA+AA) showed a 52.1% lower incidence of early-onset breast cancer in Uygur women (OR = 0.479, 95%CI = 0.230 - 0.995). Stratified analysis indicated that the protective effect of carrying T variant genotype (CT/TT) in Pro24Ser and carrying C variant genotype (GC/CC) in Arg378Ser were more evident in subjects with early age at menarche and negative family history of cancer. With an older menarche age, the protective effect was weaker. CONCLUSIONS: SNPs of Pro24Ser(C/T), Arg378Ser (G/C) and Val507Met (G/A) of BARD1 gene are associated with significantly decreased risk of early-onset breast cancer in Uygur women in Xinjiang. Early age at menarche and negative family history of cancer can enhance the protective effect of mutant allele.