Carolina Batista Ariza

Molecular Markers for Breast Cancer: Prediction on Tumor Behavior

Breast cancer is one of the most common cancers with greater than 1,300,000 cases and 450,000 deaths each year worldwide. The development of breast cancer involves a progression through intermediate stages until the invasive carcinoma and finally into metastatic disease. Given the variability in clinical progression, the identification of markers that could predict the tumor behavior is particularly important in breast cancer. The determination of tumor markers is a useful tool for clinical management in cancer patients, assisting in diagnostic, staging, evaluation of therapeutic response, detection of recurrence and metastasis, and development of new treatment modalities. In this context, this review aims to discuss the main tumor markers in breast carcinogenesis. The most well-established breast molecular markers with prognostic and/or therapeutic value like hormone receptors, HER-2 oncogene, Ki-67, and p53 proteins, and the genes for hereditary breast cancer will be presented. Furthermore, this review shows the new molecular targets in breast cancer: CXCR4, caveolin, miRNA, and FOXP3, as promising candidates for future development of effective and targeted therapies, also with lower toxicity.

CC Chemokine Receptor 5: The Interface of Host Immunity and Cancer

Solid tumors are embedded in a stromal microenvironment consisting of immune cells, such as macrophages and lymphocytes, as well as nonimmune cells, such as endothelial cells and fibroblasts. Chemokines are a type of small secreted chemotactic cytokine and together with their receptors play key roles in the immune defense. Critically, they regulate cancer cellular migration and also contribute to their proliferation and survival. The CCR5 chemokine receptor is involved in leucocytes chemotaxis to sites of inflammation and plays an important role in the macrophages, T cells, and monocytes recruitment. Additionally, CCR5 may have an indirect effect on cancer progression by controlling the antitumor immune response, since it has been demonstrated that its expression could promote tumor growth and contribute to tumor metastasis, in different types of malignant tumors. Furthermore, it was demonstrated that a CCR5 antagonist may inhibit tumor growth, consisting of a possible therapeutic target. In this context, the present review focuses on the establishment of CCR5 within the interface of host immunity, tumor microenvironment, and its potential as a targeting to immunotherapy.

FOXP3 transcription factor: a candidate marker for susceptibility and prognosis in triple negative breast cancer.

Triple negative breast cancer (TNBC) is a relevant subgroup of neoplasia which presents negative phenotype of estrogen and progesterone receptors and has no overexpression of the human epidermal growth factor 2 (HER2). FOXP3 (forkhead transcription factor 3) is a marker of regulatory T cells (Tregs), whose expression may be increased in tumor cells. This study aimed to investigate a polymorphism (rs3761548) and the protein expression of FOXP3 for a possible involvement in TNBC susceptibility and prognosis. Genetic polymorphism was evaluated in 50 patients and in 115 controls by allele-specific PCR (polymerase chain reaction). Protein expression was evaluated in 38 patients by immunohistochemistry. It was observed a positive association for homozygous AA (OR = 3.78; 95% CI = 1.02–14.06) in relation to TNBC susceptibility. Most of the patients (83%) showed a strong staining for FOXP3 protein in the tumor cells. In relation to FOXP3-positive infiltrate, 47% and 58% of patients had a moderate or intense intratumoral and peritumoral mononuclear infiltrate cells, respectively. Tumor size was positively correlated to intratumoral FOXP3-positive infiltrate (P = 0.026). In conclusion, since FOXP3 was positively associated with TNBC susceptibility and prognosis, it seems to be a promising candidate for further investigation in larger TNBC samples.

STin2 VNTR polymorphism is associated with comorbid tobacco use and mood disorders

BACKGROUND There is a significant comorbidity between mood disorders and tobacco use disorder (TUD), which may be related to both genetic and environmental factors. Gene variants of the 5-HT transporter, such as STin2 VNTR (a variable number of tandem repeats in the functional serotonin transporter intron 2) may be associated with mood disorders and TUD. AIMS This study aimed to delineate the association between the STin2 genetic polymorphism and comorbid TUD and mood disorders, including depression or bipolar disorder. METHODS We examined the STin2 VNTR polymorphism in never-smokers (n=113); patients with mood disorders without TUD (n=62); patients with TUD without mood disorders (n=90); and patients with both disorders (n=95). RESULTS We found a significant association between the STin2 genetic polymorphism and the above diagnostic groups whereby the STin2.12 allele shows a positive association with comorbid TUD and mood disorders (Odds ratio=3.07, 95% CI=1.41-6.68), while the STin2.10/10 homozygous genotype shows a negative association (Odds ratio=0.34, 95% CI=0.16-0.74). Adjusting for years of education, age, gender, marital status and ethnicity did not change these results, but showed that TUD was associated with lower education levels and less stable relationships, whereas mood disorders were related to female gender. A family history of TUD was significantly associated with TUD in subjects without mood disorders only. CONCLUSIONS The STin2.12 allele is positively and the STin2.10/10 genotype is negatively associated with comorbid TUD and mood disorders, depression or bipolar depression, suggesting that biological endophenotypes, e.g. disorders in serotonin metabolism, may in part underpin this comorbidity.

Role of CXCL12 and CXCR4 in normal cerebellar development and medulloblastoma

Chemokines and its receptors have significant impact on physiological and pathological processes and studies concerning their association with tumor biology are subject of great interest in scientific community. CXCL12/CXCR4 axis has been widely studied due to its significant role in tumor microenvironment, but it is also important to development and maintenance of tissues and organs, for example, in the brain and cerebellum. Studies have demonstrated that CXCL12 and CXCR4 are required for normal cerebellar development and that dysfunction in this pathway may be involved with medulloblastoma pathogenesis. In this context, a new molecular subgroup has been suggested based on the importance of the association between CXCR4 overexpression and sonic hedgehog subgroup. Treatment using CXCR4 antagonists showed significant results, evidencing the important role and possible therapeutic capacity of CXCR4 in MB. This review summarizes studies on MB cell biology, focusing on a chemokine‐receptor axis, CXCL12/CXCR4, that may have implications for treatment strategies once it can improve life expectancy and reduce neurocognitive sequelae of patients with this neoplasia.

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.

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.

Inulin Induces IL-10 Secretion and Increased FOXP3 Gene Expression in Human Peripheral Blood Mononuclear Cells

Inulin is an effective prebiotic and its potential in modulating systemic immunity have been proposed. A subpopulation of T cells, named T regulatory cells (Tregs), expressing the Forkhead boxP3 transcription factor are key mediators of peripheral tolerance and suppress undesirable immune responses. These Tregs can be induced by cytokine transforming growth factor beta (TGF-β) and interleukin 10 (IL-10). This work aimed to evaluate inulin effects on human peripheral blood mononuclear cells (PBMC) in vitro. PBMC were incubated with inulin, and the expression of TGF-1, FOXP3 and IL-10 was analyzed. Increased supernatant IL-10 levels were observed in PBMC of inulin-treated group (p=0.03). Moreover, FOXP3 gene expression was 7.6 fold higher in inulin-treated PBMC, whereas a trend in TGF-β1 expression was detected (p=0.055). These data suggest that inulin induces an immunosuppressive environment in cultured PBMC by promoting FOXP3 gene expression and IL-10 secretion. These studies offer prospects for further fundamental research in this field.

The predictive value of transforming growth factor-β in Wilms tumor immunopathogenesis

ABSTRACT Wilms tumor is the most common kidney malignancy in children, especially in children aged less than 6 years. Although therapeutic approach has reached successful rates, there is still room for improvement. Considering the tumor microenvironment, cytokines represent important elements of interaction and communication between tumor cells, stroma, and immune cells. In this regard, the transforming growth factor beta (TGF-β) family members play significant functions in physiological and pathological conditions, particularly in cancer. By regulating cell growth, death, and immortalization, TGF-β signaling pathways exert tumor suppressor effects in normal and early tumor cells. Thus, it is not surprising that a high number of human tumors arise due to alterations in genes coding for various TGF-β signaling components. Understanding the ambiguous role of TGF-β in human cancer is of paramount importance for the development of new therapeutic strategies to specifically block the metastatic signaling pathway of TGF-β without affecting its tumor suppressive effect. In this context, this review attempt to summarize the involvement of TGF-β in Wilms tumor.

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.