Glauco Akelinghton Freire Vitiello

Genetic Polymorphism and Expression of CXCR4 in Breast Cancer.

CXCR4 genetic polymorphisms, as well as their expression level, have been associated with cancer development and prognosis. The present study aimed to investigate the influence of CXCR4 rs2228014 polymorphism on its mRNA and protein expression in breast cancer samples. It was observed that patients presented higher CXCR4 mRNA relative expression (5.7-fold) than normal mammary gland, but this expression was not correlated with patients clinicopathological features (nuclear grade, nodal status, ER status, PR status, p53 staining, Ki67 index, and HER-2 status). Moreover, CXCR4 mRNA relative expression also did not differ regarding the presence or absence of T allele (p = 0.301). In the immunohistochemical assay, no difference was observed for CXCR4 cytoplasmic protein staining in relation to different genotypes (p = 0.757); however, high cytoplasmic CXCR4 staining was verified in invasive breast carcinoma (p < 0.01). All in all, the results from present study indicated that rs2228014 genetic variant does not alter CXCR4 mRNA or protein expression. However, this receptor was more expressed in tumor compared to normal tissue, in both RNA and protein levels, suggesting its promising applicability in the general context of mammary carcinogenesis.

The prognostic value of regulatory T cells infiltration in HER2-enriched breast cancer microenvironment

ABSTRACT Breast cancer represents a complex and heterogeneous disease that comprises distinct disease conditions, histological features, and clinical outcome. Since many years, it has been demonstrated as an association between HER2 amplification and poor prognosis, because its overexpression is associated with an aggressive phenotype of breast tumor cells. A significant proportion of cases have developed resistance to the current therapies available. Consequently, new prognostic markers are urgently needed to identify patients who are at the highest risk for developing metastases. During the past decade, new insights provided valuable knowledge regarding mechanisms underlying the dynamic interplayed between immune cells and tumor progression. It has been shown that the presence of a lymphocytic infiltrate, particularly of regulatory T cells, in cancer tissue, is associated with clinical outcome promoting rather than inhibiting cancer development and progression. It has been also verified that the clinical value of lymphocytic infiltration in breast cancers could be subtype-dependent, including the HER2-enriched subtype. In this context, this work summarizes proposed to discuss the prognostic value of regulatory T cell infiltration in microenvironment of HER2-enriched breast cancer.

FOXP3 Allelic Variants and Haplotype Structures Are Associated with Aggressive Breast Cancer Subtypes

FOXP3 genetic polymorphisms have been associated with cancer development and prognosis. In this context, the present study aimed to evaluate the g.10403A>G (rs2232365) polymorphisms and g.8048A>C (rs3761548), in aggressive breast cancer (BC) subtypes, including, Luminal B HER2+ (LB), HER2-enriched (HER2+), and triple-negative (TN). Polymerase chain reaction followed by enzymatic restriction was performed to genotyping 117 BC samples and 300 controls. A significant association of AA genotype (g.10403A>G) in relation to BC susceptibility (OR = 1.93; 95% CI = 1.01–3.66; p = 0.046) was observed. The GG (g.10403A>G) genotype was correlated with higher proliferation index (Ki-67) in HER2+ subtype (τ = 0.47; p = 0.019) and advanced TNM staging in TN (τ = 0.23; p = 0.032). A correlation of AA genotype (g.8048A>C) with higher Ki-67 (τ = −0.47; p = 0.018) and lower histological grade (τ = 0.39; p = 0.026) in HER2+ was also found. GA haplotype was correlated with lower histological grade (τ = −0.15; p = 0.009) and higher Ki-67 (τ = 0.43; p = 0.036) in HER2+ and advanced staging in TN (τ = 0.29; p = 0.044). On the other hand, AC haplotype was correlated with lower Ki-67 (τ = −0.54; p = 0.005) and staging (τ = −0.29; p = 0.027) in HER2+ and TN respectively. Results showed that FOXP3 influence regarding clinical outcome depends greatly on the BC subtype and indicated this transcription factor as a promising marker in aggressive BC subtypes.

Interleukin 7 receptor alpha Thr244Ile genetic polymorphism is associated with susceptibility and prognostic markers in breast cancer subgroups

Abstract Interleukin‐7 (IL‐7) exerts crucial functions on lymphoid cells’ development and maintenance. In breast cancer (BC), IL‐7 promotes growth of tumor cells in culture through the activation of JAK1/3‐STAT5 and PI3K/AKT pathways, and expression of IL‐7 signaling components was associated with worst prognosis. A C>T polymorphism (rs6897932; Thr244Ile) at exon 6 of IL‐7 receptor alpha (IL‐7R&agr;) gene (IL7RA) shifts the balance between the membrane‐bound and soluble IL‐7R&agr; splicing variants and was previously associated with autoimmune diseases, but has not been studied in cancer, including BC, so far. Therefore, the present study aimed to investigate the possible association of this polymorphism with the susceptibility and clinicopathological parameters of BC subgroups. IL7RA Thr244Ile was genotyped through PCR‐RFLP in 403 women without neoplasia, no personal history of malignancy or family history of BC and in 338 BC patients with clinicopathological data available. BC patients were stratified according to their positivity for estrogen (ER) and/or progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Age‐adjusted logistic regression was performed for case‐control analyses, and correlations with clinicopathological parameters were assessed through Kendall’s Tau‐b coefficient. All analyses were two‐tailed and had 95% confidence interval. In ER−PR−HER2− BCs, TT genotype was associated with increased susceptibility both in genotypic (TT vs. CC: OR = 3.07; CI = 1.01–9.38; p = 0.05) and recessive (TT vs. CC + CT: OR = 3.59; CI = 1.19–10.85; p = 0.02) models and negatively correlated with disease stage (Tau‐b = −0.27; p = 0.05). Whereas T allele was positively correlated with histopathological grade (Tau‐b = 0.29; p = 0.03) and lymph node metastasis (Tau‐b = 0.35; p = 0.02) in ER/PR+HER2+BCs and with Ki67 (Tau‐b = 0.51; p = 0.008) in ER−PR−HER2+ subgroup. These data indicate that IL‐7R&agr; is involved in BC, and that IL7RA polymorphism may play distinct roles in breast carcinogenesis according to BC subtype, pointing this genetic variant as an interesting marker for breast carcinogenesis to be validated by further mechanistic and prospective studies with larger samples.

Absence of Association between CCR5 rs333 Polymorphism and Childhood Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is a malignant disorder that originates from one single hematopoietic precursor committed to B- or T-cell lineage. Ordinarily, these cells express CCR5 chemokine receptor, which directs the immune response to a cellular pattern and is involved in cancer pathobiology. The genetic rs333 polymorphism of CCR5 (Δ32), results in a diminished receptor expression, thus leading to impaired cell trafficking. The objective of the present study was to investigate the effect of CCR5 chemokine receptor rs333 polymorphism in the pathogenesis of ALL. The genotype distribution was studied in 79 patients and compared with 80 control subjects, in a childhood population of Southern Brazil. Genotyping was performed using DNA samples amplified by polymerase chain reaction with sequence-specific primers (PCR-SSP). The homozygous (Δ32/Δ32) deletion was not observed in any subject involved in the study. Heterozygous genotype was not associated with ALL risk (OR 0.7%; 95% CI 0.21–2.32; P > 0.05), nor recurrence status of ALL (OR 0.86; 95% CI 0.13–5.48; P > 0.05). This work demonstrated, for the first time, no significant differences in the frequency of the CCR5/Δ32 genotype between ALL and control groups, indicating no effect of this genetic variant on the ALL susceptibility and recurrence risk.

HER2 Ile655Val polymorphism is negatively associated with breast cancer susceptibility

The HER2 (human epidermal growth factor receptor‐2) Ile655Val (rs1136201) genetic polymorphism can alter the receptor structure and its auto‐activation, which can modify the signal transduction and, consequently, the cell cycle regulation. For this reason, this polymorphism has been extensively investigated as a candidate marker for breast cancer (BC). In this context, the aim of this study was to evaluate the possible influence of HER2 Ile655Val in BC susceptibility and prognostic factors in a Brazilian population.

Potential use of CXCL12/CXCR4 and sonic hedgehog pathways as therapeutic targets in medulloblastoma

Abstract Medulloblastoma (MB) is the most common malignant brain tumor occurring in children, and although high long-term survival rates have been reached with current therapeutic protocols, several neurological injuries are still observed among survivors. It has been shown that the development of MB is highly dependent on the microenvironment surrounding it and that the CXCL12 chemokine and its receptor, CXCR4 and the Sonic Hedgehog (SHH) pathway are crucial for cerebellar development, coordinating proliferation and migration of embryonic cells and malfunctions in these axes can lead to MB development. Indeed, the concomitant overactivation of these axes was suggested to define a new MB molecular subgroup. New molecules are being studied, aiming to inhibit either CXCR4 or the SHH pathways and have been tested in preclinical settings for the treatment of cancers. The use of these molecules could improve MB treatment and save patients from aggressive surgery, chemotherapy and radiotherapy regimens, which are responsible for severe neurological consequences. This review aims to summarize current data about the experimental inhibition of CXCR4 and SHH pathways in MB and its potential implications in treatment of this cancer.

Involvement of transforming growth factor beta-1 (TGFβ1) cytokine and FOXP3 transcription factor genetic polymorphisms in hematological malignancies

Hematological malignancies (HM) are a group of neoplastic diseases that arise from hematologic cell lineages. Transforming growth factor beta 1 (TGFβ1) is shown to negatively regulate normal and malignant hematopoiesis and, in immunological context, to promote T cell exhaustion and generation of regulatory T cells, which are shown to be deleterious in cancer, by the induction of transcription factor FOXP3 expression. The present study aimed to evaluate TGFB1 exon-1 rs1800470 and FOXP3 intron-1 rs2232365 polymorphisms in relation to HM susceptibility. DNA was extracted from blood samples of 43 HM patients and 142 neoplasia-free individuals and polymorphisms were analyzed by allelic-specific PCR. Association analysis was assessed by the Odds Ratio (OR) with significance level of 5%. Regarding FOXP3 polymorphism, no significant differences were observed in genotype or allele distribution among the patients and controls. However, there was a positive association between TGFB1 TT genotype and HM susceptibility (OR = 4.07; CI95% = 1.94 - 8.52). In the combined analysis, a positive association was also observed for TGFB1 TT and FOXP3 GG genotypes (OR = 4.00; CI95% = 1.54 - 10.41) in relation to HM susceptibility. Our results indicated promising new markers to be further investigated in hematological malignancies.

Protein Expression and Codon 72 Polymorphism of TP53 Gene in Triple Negative Breast Cancer

A subgroup of tumor that has received attention is triple-negative breast cancer (TNBC), which presents phenotype of negative estrogen receptor, negative progesterone receptor and has no overexpression of HER2. TP53 acts as a tumor suppressor limiting the proliferation of damaged cells. A polymorphic site (rs1042522) of TP53 encodes either an arginine or a proline amino acid, but its biological significance remains unclear. This study aimed to investigate this variant and its expression in search for a possible involvement in TNBC susceptibility and clinical outcome. Genetic polymorphism was evaluated in 50 patients and 115 controls by PCR based methodology and immunohistochemistry was done with monoclonal antibody. Case-control study showed no positive or negative association (OR= 0.95; CI95%= 0.48-1.89). Comparison of genotypes and clinical outcome showed no significant results. Despite most of patients presented p53 positive staining by immunohistochemistry, there was no significant association in relation to prognostic parameters. Results demonstrated a lack of association between codon 72 polymorphism, susceptibility and prognosis of TNBC. Immunohistochemistry analysis should be done more carefully, since most of the patients had the somatic mutation of p53, which could be an indicator of prognostic value in TNBC.

TGF-β polymorphism and its expression correlated with CXCR4 expression in human breast cancer.

Background It is known that the transforming growth factor beta (TGF-b) can act as both a tumor suppressor and as a significant stimulator of tumor progression, invasion, and metastasis. It has been suggested a link between TGF-b and CXCR4 expression in human breast cancer cells, which may be one of the mechanisms of TGF-b mediated enhancement of metastatic potential in breast cancer cells. Therefore, the objective of the present study was to investigate the TGF-b T869C polymorphism and its expression correlated with CXCR4 expression in breast cancer patients.