Interferon-gamma plasma levels and presence of mouse mammary tumor virus-like env gene: Implications on the pathogenesis of breast cancer.

Mouse mammary tumor virus (MMTV) is a retrovirus that has been associated with the development of breast cancer (BC) in mice. The identification of a 95% homologous gene sequence to MMTV in human BC samples has increased interest in this hypothesis. This virus in humans received the name of mouse mammary tumor virus-like (MMTV-like). Several cytokines may be involved in the interactions between MMTV and the immune system, such as interferon-gamma (IFN-γ), which can enhance Th1-mediated antitumor immune response but it can also play a protumorigenic role by transmitting antiapoptotic and proliferative signals. Little is known about the antiviral immune response in a microenvironment with the presence of MMTV-like in BC patients. Therefore, the purpose of the present study was to quantify the plasma levels of IFN-γ in the peripheral blood of 123 neoplasia-free donors and 98 BC patients of different molecular subtypes, by enzyme-linked immunosorbent assay (ELISA), and evaluate the association of these plasma levels with the detection of the MMTV-like env gene in tumor tissue. Correlation analyzes involving IFN-γ plasma levels and clinical-pathological parameters were performed by Kendall Tau-c test. In our study, a decrease in IFN-γ levels was observed in the group of BC patients (30.85 ± 57.49 pg/ml) compared to the control group (115.00 ± 176.80 pg/ml) (p < 0.0001). In the analysis by stratified BC molecular subtypes, Luminal-A (30.79 ± 61.04 pg/ml; p < 0.0001), Luminal-B (24.74 ± 25.78 pg/ml; p = 0.0188) and triple-negative (23.95 ± 40.45 pg/ml; p = 0.0005) had a lower plasma level compared to control group. There was no significant difference between IFN-γ plasma levels of MMTV-like DNA positive samples compared to MMTV-negative samples (p = 0.2056). In general BC, patients with larger tumor size had higher IFN-γ plasma levels (Tau-c = 0.202; p = 0.019). By analyzing the MMTV-like env negative samples, we could identify that IFN-γ plasma levels were higher in larger tumor size (Tau-c = 0.222; p = 0.020) and with greater lymph node involvement (Tau-c = 0.258; p = 0.042). Also, higher IFN-γ plasma levels were observed in patients with higher histopathological grades (Tau-c = 0.384; p = 0.019) in MMTV-like env positive samples. For the first time, we assessed the association between plasma levels of IFN-γ and the presence of the MMTV-like env gene in BC samples. However, more studies are needed to clarify whether the high levels of IFN-γ in MMTV-like env positive samples are reflecting a possible antiviral immune response or whether this cytokine is promoting tumor growth.

APOBEC3A/B Polymorphism Is Not Associated with Human Papillomavirus Infection and Cervical Carcinogenesis.

The persistence of a high-risk Human papillomavirus (HPV-HR) infection of the cervix results in different manifestations of lesions depending on the immunologic capacity of the host. Variations in apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC)-like genes, such as the APOBEC3A/B deletion hybrid polymorphism (A3A/B), may contribute to cervical malignancy in the presence of HPV. The aim of this study was to investigate the association between the A3A/B polymorphism and HPV infection and the development of cervical intraepithelial lesions and cervical cancer in Brazilian women. The study enrolled 369 women, who were categorized according to the presence of infection and subdivided according to the degree of intraepithelial lesion and cervical cancer. APOBEC3A/B was genotyped by allele-specific polymerase chain reaction (PCR). As for the A3A/B polymorphism, the distribution of genotypes was similar between groups and among the analyzed subgroups. There were no significant differences in the presence of infection or development of lesions, even after exclusion of confounding factors. This is the first study to show that the A3A/B polymorphism is not associated with HPV infection and the development of intraepithelial lesions and cervical cancer in Brazilian women.

Mature tertiary lymphoid structures are key niches of tumour-specific immune responses in pancreatic ductal adenocarcinomas.

OBJECTIVE: To better understand the immune microenvironment of pancreatic ductal adenocarcinomas (PDACs), here we explored the relevance of T and B cell compartmentalisation into tertiary lymphoid structures (TLSs) for the generation of local antitumour immunity. DESIGN: We characterised the functional states and spatial organisation of PDAC-infiltrating T and B cells using single-cell RNA sequencing (scRNA-seq), flow cytometry, multicolour immunofluorescence, gene expression profiling of microdissected TLSs, as well as in vitro assays. In addition, we performed a pan-cancer analysis of tumour-infiltrating T cells using scRNA-seq and sc T cell receptor sequencing datasets from eight cancer types. To evaluate the clinical relevance of our findings, we used PDAC bulk RNA-seq data from The Cancer Genome Atlas and the PRINCE chemoimmunotherapy trial. RESULTS: We found that a subset of PDACs harbours fully developed TLSs where B cells proliferate and differentiate into plasma cells. These mature TLSs also support T cell activity and are enriched with tumour-reactive T cells. Importantly, we showed that chronically activated, tumour-reactive T cells exposed to fibroblast-derived TGF-ß may act as TLS organisers by producing the B cell chemoattractant CXCL13. Identification of highly similar subsets of clonally expanded CXCL13 + tumour-infiltrating T cells across multiple cancer types further indicated a conserved link between tumour-antigen recognition and the allocation of B cells within sheltered hubs in the tumour microenvironment. Finally, we showed that the expression of a gene signature reflecting mature TLSs was enriched in pretreatment biopsies from PDAC patients with longer survival after receiving different chemoimmunotherapy regimens. CONCLUSION: We provided a framework for understanding the biological role of PDAC-associated TLSs and revealed their potential to guide the selection of patients for future immunotherapy trials.

Involvement of APOBEC3A/B Deletion in Mouse Mammary Tumor Virus (MMTV)-like Positive Human Breast Cancer.

The association between mouse mammary tumor virus (MMTV)-like sequences and human breast cancer (BC) is largely documented in the literature, but further research is needed to determine how they influence carcinogenesis. APOBEC3 cytidine deaminases are viral restriction factors that have been implicated in cancer mutagenesis, and a germline deletion that results in the fusion of the APOBEC3A coding region with the APOBEC3B 3'-UTR has been linked to increased mutagenic potential, enhanced risk of BC development, and poor prognosis. However, little is known about factors influencing APOBEC3 family activation in cancer. Thus, we hypothesized that MMTV infection and APOBEC3-mediated mutagenesis may be linked in the pathogenesis of BC. We investigated APOBEC3A/B genotyping, MMTV-like positivity, and clinicopathological parameters of 209 BC patients. We show evidence for active APOBEC3-mediated mutagenesis in human-derived MMTV sequences and comparatively investigate the impact of APOBEC3A/B germline deletion in MMTV-like env positive and negative BC in a Brazilian cohort. In MMTV-like negative samples, APOBEC3A/B deletion was negatively correlated with tumor stage while being positively correlated with estrogen receptor expression. Although APOBEC3A/B was not associated with MMTV-like positivity, samples carrying both MMTV-like positivity and APOBEC3A/B deletion had the lowest age-at-diagnosis of all study groups, with all patients being less than 50 years old. These results indicate that APOBEC3 mutagenesis is active against MMTV-like sequences, and that APOBEC3A/B deletion might act along with the MMTV-like presence to predispose people to early-onset BC.

Comprehensive analysis of epigenetics regulation, prognostic and the correlation with immune infiltrates of GPX7 in adult gliomas.

Gliomas are the most commonly occurring malignant brain tumor characterized by an immunosuppressive microenvironment accompanied by profound epigenetic changes, thus influencing the prognosis. Glutathione peroxidase 7 (GPX7) is essential for regulating reactive oxygen species homeostasis under oxidative stress. However, little is known about the function of GPX7 in gliomas. In this study, we hypothesized that GPX7 methylation status could influence biological functions and local immune responses that ultimately impact prognosis in adult gliomas. We conducted an integrated bioinformatics analysis mining GPX7 DNA methylation status, transcriptional and survival data of glioma patients. We discovered that GPX7 was remarkably increased in glioma tissues and cell lines, and was associated with poor prognosis. This upregulation was significantly linked to clinicopathological and molecular features, besides being expressed in a cell cycle-dependent manner. Our results consistently demonstrated that upregulation of GPX7 is tightly modulated by epigenetic processes, which also impacted the overall survival of patients with low-grade gliomas (LGG). Based on the analysis of biological functions, we found that GPX7 might be involved in immune mechanisms involving both innate and adaptive immunity, type I interferon production and regulation of synaptic transmission in LGG, whereas in GBM, it is mainly related to metabolic regulation of mitochondrial dynamics. We also found that GPX7 strongly correlates with immune cell infiltration and diverse immune cell markers, suggesting its role in tumor-specific immune response and in regulating the migration of immune cell types to the tumor microenvironment. Combining these multiple data, we provided the first evidence regarding the epigenetic-mediated regulatory mechanisms underlying GPX7 activation in gliomas. Furthermore, our study brings key insights into the significant effect of GPX7 in modulating both immune molecules and in immune cell infiltration in the microenvironment of gliomas, which might impact the patient outcome, opening up future opportunities to regulate the local immune response.

Antiviral Responses in Cancer: Boosting Antitumor Immunity Through Activation of Interferon Pathway in the Tumor Microenvironment.

In recent years, it became apparent that cancers either associated with viral infections or aberrantly expressing endogenous retroviral elements (EREs) are more immunogenic, exhibiting an intense intra-tumor immune cell infiltration characterized by a robust cytolytic apparatus. On the other hand, epigenetic regulation of EREs is crucial to maintain steady-state conditions and cell homeostasis. In line with this, epigenetic disruptions within steady-state cells can lead to cancer development and trigger the release of EREs into the cytoplasmic compartment. As such, detection of viral molecules by intracellular innate immune sensors leads to the production of type I and type III interferons that act to induce an antiviral state, thus restraining viral replication. This knowledge has recently gained momentum due to the possibility of triggering intratumoral activation of interferon responses, which could be used as an adjuvant to elicit strong anti-tumor immune responses that ultimately lead to a cascade of cytokine production. Accordingly, several therapeutic approaches are currently being tested using this rationale to improve responses to cancer immunotherapies. In this review, we discuss the immune mechanisms operating in viral infections, show evidence that exogenous viruses and endogenous retroviruses in cancer may enhance tumor immunogenicity, dissect the epigenetic control of EREs, and point to interferon pathway activation in the tumor milieu as a promising molecular predictive marker and immunotherapy target. Finally, we briefly discuss current strategies to modulate these responses within tumor tissues, including the clinical use of innate immune receptor agonists and DNA demethylating agents.

Genetic Polymorphisms of the TGFB1 Signal Peptide and Promoter Region: Role in Wilms Tumor Susceptibility?

The aim of the present study was to investigate the rs1800468 (G-800A), rs1800469 (C-509T), rs1800470 (C29T), and rs1800471 (G74C) TGFB1 genetic polymorphisms and their haplotype structures in patients with Wilms Tumor (WT) and neoplasia-free controls. The genomic DNA was extracted from 35 WT patients and 160 neoplasia-free children, and the TGFB1 polymorphisms were genotyped by polymerase chain reaction, followed by restriction fragment length polymorphism. The haplotype structures were inferred, and permutation and logistic regression tests were performed to check for differences in haplotype distribution between the control and WT individuals. Positive associations were found in the recessive model for rs1800469 T allele (OR: 8.417; 95% CI: 3.177 to 22.297; P < 0.001) and for the rs1800470 C allele (OR: 3.000; 95% CI: 1.296 to 6.944; P = 0.01). Haplotype analysis revealed a significant negative association between GCTG and WT (OR: 0.236, 95% CI: 0.105 to 0.534; P = 0.0002); by contrast, the GTTG haplotype was associated with increased risk for WT (OR: 12.0; 95% CI: 4.202 to 34.270; P < 0.001). Furthermore, rs1800469 was negatively correlated with tumor size and a trend toward a positive correlation for capsular invasion was observed in the dominant model (Tau-b: -0.43, P = 0.02 and tau-b: 0.5, P = 0.06, respectively). This is the first study with rs1800468, rs1800469, rs1800470, and rs1800471 TGFB1 polymorphisms in WT, and our results suggest that the TGFB1 promoter and signal peptide region polymorphisms may be associated with WT susceptibility and clinical presentation.

Transforming growth factor beta 1 (TGFß1) plasmatic levels and haplotype structures in obesity: a role for TGFß1 in steatosis development.

BACKGROUND: Obesity is considered a chronic inflammatory disease and transforming growth factor beta 1 (TGFß1) might exert important roles in disease pathogenesis regulating adipocyte differentiation and immune-inflammatory environment. However, the role of this cytokine as a biomarker in obesity is poorly addressed. Therefore, the present study aimed to evaluate the impact of TGFB1 polymorphisms and TGFß1 plasmatic levels in obesity METHODS AND RESULTS: TGFB1 promoter region polymorphisms (rs1800468, G-800A and rs1800469, C-509 T) were evaluated in 75 obese patients and 45 eutrophic patients through PCR-RFLP and plasmatic TGFß1 was quantified through ELISA from 37 of the obese patients, and correlations with clinical and biochemical parameters were tested. Despite no association was found between TGFB1 polymorphisms and obesity susceptibility, several correlations with clinical data were noted. Among others, AC haplotype negatively correlated with plasmatic TGFß1, while plasmatic TGFß1 negatively correlated with C-reactive protein and positively correlated with liver abnormalities on ultrasound and, specifically, with steatosis presence and degree. Conversely, GT haplotype, which associates with higher TGFß1 production, was also positively correlated with the same parameters of liver abnormalities. Further, plasmatic vitamin D negatively correlated with TGFß1, while positively correlated with AC haplotype. CONCLUSION: Overall, the results indicate that TGFß1 might exert important roles in obesity pathophysiology and correlate with biochemical and clinical parameters both at systemic protein as well as at genetic level. Importantly, the consistent positive correlation at both levels with steatosis might suggest this cytokine as a biomarker for this hepatic abnormality in obese patients.

B Cell Orchestration of Anti-tumor Immune Responses: A Matter of Cell Localization and Communication.

The immune system plays a crucial role in cancer development either by fostering tumor growth or destroying tumor cells, which has open new avenues for cancer immunotherapy. It was only over the last decade that the role of B cells in controlling anti-tumor immune responses in the tumor milieu has begun to be appreciated. B and plasma cells can exert anti-tumor effects through antibody-dependent cell cytotoxicity (ADCC) and activation of the complement cascade, even though their effector functions extend beyond the classical humoral immunity. In tumor tissues, B cells can be found in lymphoid aggregates, known as tertiary lymphoid structures (TLSs), well-organized non-encapsulated structures composed of immune and stromal cells. These structures reflect a process of lymphoid neogenesis occurring in peripheral tissues upon long-lasting exposure to inflammatory signals. The TLS provides an area of intense B cell antigen presentation that can lead to optimal T cell activation and effector functions, as well as the generation of effector B cells, which can be further differentiated in either antibody-secreting plasma cells or memory B cells. Of clinical interest, the crosstalk between B cells and antigen-experienced and exhausted CD8+ T cells within mature TLS was recently associated with improved response to immune checkpoint blockade (ICB) in melanoma, sarcoma and lung cancer. Otherwise, B cells sparsely distributed in the tumor microenvironment or organized in immature TLSs were found to exert immune-regulatory functions, inhibiting anti-tumor immunity through the secretion of anti-inflammatory cytokines. Such phenotype might arise when B cells interact with malignant cells rather than T and dendritic cells. Differences in the spatial distribution likely underlie discrepancies between the role of B cells inferred from human samples or mouse models. Many fast-growing orthotopic tumors develop a malignant cell-rich bulk with reduced stroma and are devoid of TLSs, which highlights the importance of carefully selecting pre-clinical models. In summary, strategies that promote TLS formation in close proximity to tumor cells are likely to favor immunotherapy responses. Here, the cellular and molecular programs coordinating B cell development, activation and organization within TLSs will be reviewed, focusing on their translational relevance to cancer immunotherapy.

Expression of Ki67 and p53 Proteins: Breast Cancer Aggressivity Markers in Brazilian Young Patients.

Background: The increase in breast cancer (BC) cases in young women is of great importance since the tumor behavior in this group is generally more aggressive than in their older counterparts, and strategies for early diagnosis and prognostication are needed. Therefore, this work sought to investigate prognostic markers associated with young (<44 years old) BC patients. Methods: Two hundred thirty-six primary tumor tissues from 232 BC patients, of which 44 had less than 44 years at diagnosis were evaluated regarding the expression of estrogen and progesterone receptors (ER and PR), human epidermal growth factor receptor 2 (HER2), Ki67, and p53 (used as an indicator of p53 mutations) through immunohistochemistry. Also, data regarding tumor size, histopathological grade (HG), lymph node metastasis disease stage, and patients' survival status were collected. Results: Early age tumors had higher Ki67 expression and p53 mutations, and these markers were positively correlated with each other and associated worse prognosis parameters, such as negativity for ER and PR and positivity for HER2, and with higher HG, tumor size, and disease stage. In young patients, Ki67 correlated with ER, PR, and HG, whereas p53 correlated with HER2 and disease stage. Also, Ki67 associated with BC death independently of time from diagnosis, patients age, tumor size, and disease stage, and showed a trend toward a positive correlation with death in young patients, but not in the older group. Conclusion: Young BC patients were more likely to have intensely proliferative tumors with p53 mutations and these markers may hold prognostic relevance in BC, especially in this subgroup of patients.

Germline APOBEC3B deletion influences clinicopathological parameters in luminal-A breast cancer: evidences from a southern Brazilian cohort.

PURPOSE: APOBEC3A and APOBEC3B cytidine deaminases have been implicated in the pathogenesis of multiple cancers, including breast cancer (BC). A germline deletion linking APOBEC3A and APOBEC3B loci (A3A/B) has been associated with higher APOBEC-mediated mutational burden, but its association with BC risk have been controversial. Therefore, this study investigated the association between A3A/B and BC susceptibility and clinical presentation in a Brazilian cohort. METHODS: A3A/B deletion was evaluated through allele-specific PCR in 341 BC patients and 397 women without familial or personal history of neoplasia from Brazil and associations with susceptibility to BC subtypes were tested through age-adjusted logistic models while correlations with clinicopathological parameters were tested using Kendall's tests. RESULTS: No association was found between A3A/B and BC susceptibility; however, in Luminal-A BCs, it was positively correlated with tumor size (Tau-c = 0.125) and Ki67 (Tau-c = 0.116) and negatively correlated with lymph node metastasis (LNM) (Tau-c = - 0.162). The negative association between A3A/B with LNM in Luminal-A BCs remained significant even after adjusting for tumor size and Ki67 in logistic models (OR = 0.22; p = 0.008). CONCLUSION: These results show that although A3A/B may not modify BC susceptibility in Brazilian population, it may affect clinicopathological features in BC subtypes, promoting tumor cell proliferation while being negatively associated with LNM in Luminal-A BCs.

Transforming growth factor beta 1 (TGFß1) plasmatic levels in breast cancer and neoplasia-free women: Association with patients' characteristics and TGFB1 haplotypes.

Transforming growth factor beta 1 (TGFß1) is a pleiotropic cytokine that acts in a context-dependent manner. In breast cancer (BC) this cytokine exerts subtype- and stage-specific roles, inhibiting poorly aggressive tumors while enhances the invasive potential of highly aggressive cancers. Single-nucleotide polymorphisms (SNPs) affecting TGFß1 production largely reflect this pattern of association, but studies investigating systemic TGFß1 levels in BC patients and their association with clinical features or SNPs produced conflicting conclusions. Therefore, the present work investigated plasmatic TGFß1 levels through enzyme linked immunosorbent assay (ELISA) in 341 individuals previously genotyped for four TGFB1 SNPs [G-800A (rs1800468), C-509T (rs1800469), T29C (rs1800470) and G74C (rs1800471)], encompassing 184 neoplasia-free women with clinical information regarding health status, 113 treatment-free pre-surgery BC patients and 44 treated BC patients. Results have shown that TGFß1 levels varied greatly in function of health status in neoplasia-free women, and disease-free individuals had higher TGFß1 levels than both treatment-free or treated BC patients. There was no correlation between TGFß1 with clinicopathological features in treatment-free BC general group, but it was negatively correlated with tumor size in luminal-B-HER2+ patients and with histopathological grade in triple-negative group. Also, TGFB1 ACTG haplotype (from G-800A to G74C) was associated with decreased TGFß1 levels compared to the reference GCTG haplotype, and regression analyses showed that this association was independent of age, health status or BC diagnosis. In conclusion, several factors may influence TGFß1 levels, and ACTG haplotype seems to be an important factor regulating TGFß1 production.

CCR5 and CXCL12 allelic variants: Possible association with childhood neuroblastoma susceptibility?

Neuroblastoma (NB) is a heterogeneous and particularly malignant childhood neoplasm in its higher stages, prone to form metastasis in selected organs and for which there is still no efficient treatment available beyond surgery. Evidence indicates that chemokines and their receptors present involvement as mediators of neuroinflammation and have a neurophysiological role. In the present study, we aimed to verify if CCR5 (rs333) and CXCL12 (rs1801157) allelic variants were associated with NB. For CCR5 (rs333) D32 carriers (OR: 5.96, IC: 2.21-16.06) and for CXCL12 genotype 3'A/3'A (OR:26.18, IC:6.15-111.4) there were statistically significant differences as well to allelic frequency (OR:4.20, IC: 2.19-8.03). Although no correlation was verified regarding prognostic parameters for both CCR5 and CXCL12 polymorphic variants, these polymorphisms may be associated with NB susceptibility which deserve attention for future investigations.

Transforming growth factor beta receptor II (TGFBR2) promoter region polymorphism in Brazilian breast cancer patients: association with susceptibility, clinicopathological features, and interaction with TGFB1 haplotypes.

PURPOSE: Transforming growth factor beta (TGFß) has paradoxical effects in breast cancer (BC), inhibiting initial tumors while promoting aggressive ones. A polymorphism on TGFBR2 promoter region (G-875A, rs3087465) increases TGFß type II receptor expression and is protective against cancer. Previously, we have shown that TGFB1 variants have subtype-specific roles in BC. This work sought to investigate the association between TGFBR2 and susceptibility and clinicopathological features in BC subgroups. METHODS: TGFBR2 G-875A was analyzed through PCR-RFLP in 388 BC patients and 405 neoplasia-free women. Case-control analyses as well as interaction with TGFB1 haplotypes previously associated with BC were tested through age-adjusted logistic regression. Correlations between G-875A and clinicopathological parameters were assessed through Kendall's Tau-b test. All statistical tests were two-tailed (α = 0.05). RESULTS: TGFBR2 G-875A was protective against BC in additive, genotypic, and dominant models. In subgroup-stratified analyses, these effects were greater in hormonal receptor-positive and luminal-A tumors, but were not significant in other subgroups. Logistic models including TGFB1 variants showed that in luminal-A tumors, G-875A retained its significance while TGFB1 haplotype showed a trend towards significance; otherwise, in HER2+ tumors TGFB1 variants remained significant while TGFBR2 showed a trend for association. There was no interaction between these genes. In correlation analyses, G-875A positively correlated with histopathological grade in total sample, and a trend towards significance was observed in triple-negative BCs. CONCLUSION: These results indicate that G-875A is a protective factor against BC, especially from luminal-A subtype, but may promote anaplasia in established tumors, consistent with TGFß signaling roles in BC.

Involvement of a mouse mammary tumor virus (MMTV) homologue in human breast cancer: Evidence for, against and possible causes of controversies.

Breast cancer (BC) is a complex and heterogeneous disease whose evolution depends on the tumor-host interaction. This type of cancer occurs when the mammary cells begin to grow wildly and become able to invade nearby tissues and/or promote metastases. Mouse mammary tumor virus (MMTV) is the accepted etiological agent of mammary tumors in mice. The identification of MMTV-like sequences and antigens in human mammary carcinoma has supported the theory that a virus homologous to MMTV (namely, HMTV) may be involved in human BC, but the role of retroviral elements in this disease remains elusive, as results from different research groups were contradictory. In the present review we present works for and against the involvement of HMTV in BC and discuss possible causes of divergences among studies. In the final section we fit current data regarding this issue to stablished causality criteria. We conclude that there is convincing data supporting the association of HMTV with BC, however there is still a need for epidemiological and basic research studies focusing on carcinogenic mechanisms for this virus in humans to fully understand its role in BC. This knowledge may open the way for the development of new preventive and therapeutic approaches in human BC.

CXCL12 chemokine and CXCR4 receptor: association with susceptibility and prognostic markers in triple negative breast cancer.

CXCL12/CXCR4 signaling has been implicated in breast carcinogenesis, and genetic polymorphisms in these molecules have been associated with different types of cancer. The present study analyzed genetic polymorphisms in CXCL12 (rs1801157, G > A) and CXCR4 (rs2228014, C > T) and CXCR4 immunostaining in tumor tissues from patients with triple negative breast cancer (TNBC) aiming to evaluate their possible role in its' susceptibility and prognosis. Genetic polymorphisms were analyzed in 59 TNBC patients and 150 control women; age-adjusted logistic regression showed no association when variants were considered in isolation; however, a statistically significant interaction was noted for heterozygosis for both allelic variants increasing the odds for TNBC (CXCL12-GA by CXCR4-CT: OR 7.23; 95% CI 1.15-45.41; p = 0.035). CXCL12 polymorphism was correlated negatively with proliferation index (Ki67) (Tau-b = - 0.406; p = 0.006). CXCR4 immunostaining was evaluated in 37 TNBC patients (22 with paired tumor-normal adjacent tissue). CXCR4 was detected more intensely in cell cytoplasm than in membrane, and was more expressed in tumor than in normal adjacent tissues, although not statistically significant. CXCR4 expression on the membrane of tumor cells was correlated positively with histopathological grade (Tau-b = 0.271; p = 0.036) and negatively with lymph node metastasis (Tau-b = - 0.478; p = 0.036). The present study indicates that CXCL12 and CXCR4 polymorphisms and CXCR4 immunostaining might have susceptibility and prognostic roles in TNBC pathogenesis.

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

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.

HER2 Ile655Val polymorphism is negatively associated with breast cancer susceptibility.

BACKGROUND: 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. METHODS: Polymorphism genotype was assessed through RFLP-PCR in 107 BC patients with clinicopathological data available and in 150 women with no evidence of neoplasia and with no familial history of BC as control group. Association between this polymorphism and BC susceptibility and clinical parameters was evaluated through odds ratio (OR) and chi-squared or Fisher's exact test, respectively. RESULTS: A significant negative association between valine allele and BC susceptibility in dominant model was found (OR 0.5; 95% CI 0.27-0.93, P = .036). No significant association was found in relation to BC clinicopathological features (tumor size, lymph nodes commitment, histological grade, HER2 overexpression, hormonal receptors, p53, and Ki-67). CONCLUSION: Although this polymorphism did not demonstrate potential as a prognostic marker, it may be a suitable susceptibility marker for BC.

Transforming growth factor beta 1 (TGFß1) polymorphisms and haplotype structures have dual roles in breast cancer pathogenesis.

PURPOSE: Despite the documented dual role of TGFß1 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 TGFß1 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 TGFß1 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 TGFß1 dual role in BC pathogenesis.