The PI3K/AKT/mTOR constitutes an important pathway downstream of growth factor tyrosine kinase receptors, thus regulating a plethora of biological processes as angiogenesis, proliferation, metabolism, survival, and differentiation [3]. Accumulating evidences indicate,

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in cervical tumors, being correlated with adverse clinical outcomes. EGFR may be activated by a diversity of mechanisms, including transactivation by G-protein coupled receptors (GPCRs). Studies have also shown that platelet-activating factor (PAF), a pro-inflammatory phospholipid mediator, plays an important role in the cancer progression either by modulating the cancer cells or the tumor microenvironment. Most of the PAF effects seem to be mediated by the interaction with its receptor (PAFR), a member of the GPCRs family. PAFR- and EGFR-evoked signaling pathways contribute to tumor biology; however, the interplay between them remains uninvestigated in cervical cancer. In this study, we employed The Cancer Genome Atlas (TCGA) and cancer cell lines to evaluate possible cooperation between EGFR, PAFR, and lysophosphatidylcholine acyltransferases (LPCATs), enzymes involved in the PAF biosynthesis, in the context of cervical cancer. It was observed a strong positive correlation between the expression of EGFR × PAFR and EGFR × LPCAT2 in 306 cervical cancer samples. The increased expression of LPCAT2 was significantly correlated with poor overall survival. Activation of EGFR upregulated the expression of PAFR and LPCAT2 in a MAPK-dependent fashion. At the same time, PAF showed the ability to transactivate EGFR leading to ERK/MAPK activation, cyclooxygenase-2 (COX-2) induction, and cell migration. The positive crosstalk between the PAF-PAFR axis and EGFR demonstrates a relevant linkage between inflammatory and growth factor signaling in cervical cancer cells. Finally, combined PAFR and EGFR targeting treatment impaired clonogenic capacity and viability of aggressive cervical cancer cells more strongly than each treatment separately. Collectively, we proposed that EGFR, LPCAT2, and PAFR emerge as novel targets for cervical cancer therapy.

Breast cancer is the most diagnosed cancer in women, and the second cause of cancerrelated deaths among women worldwide. It is expected that more than 240,000 new cases and 40,450 deaths related to the disease will occur in 2016. It is well known that inherited genetic variants are drivers for breast cancer development. There are many mechanisms through which germline genetic variation affects prognosis, such as BRCA1 and BRCA2 genes, which account for approximately 20% of the increased hereditary risks. Therefore, it is evident that the genetic pathways that underlie cancer development are complex in which networks of multiple alleles confer disease susceptibility and risks. Global analyses through genome-wide association studies (GWAS) have revealed several loci across the genome are associated with the breast cancer. This chapter compiles all breast GWAS released since 2007, year of the first article published in this area, and discuss the future directions of this field. Currently, hundreds of genetic markers are linked to breast cancer, and understanding the underlying mechanisms of these variants might lead to the discover of biomarkers and targets for therapy in patients.

Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) characterized by its unique molecular profile, aggressive behavior, distinct patterns of metastasis and unavailability of effective target therapy. Indeed, despite good initial response to chemotherapy, even platinum- or anthracyclines-based, TNBC relapse and mortality rates are high even in early-stage disease. Metformin, one of the most commonly used medications for treatment of type 2 diabetes mellitus, has emerged as a potential anticancer agent. This study aimed to evaluate the combination treatment of metformin, at lower concentrations (10uM), with conventional chemotherapeutic agents on TNBC cell lines. We investigated the combination effect of metformin with doxorubicin (DOX), cisplatin (CDDP) and paclitaxel (PTX). Methods: Three TNBC cell lines (MDAMB-231, HCC-70, HCC-1937) and one luminal BC cell line (MCF-7) were used. Cell proliferation was determined by MTT assay. Clonogenic assay was conducted and apoptosis was analyzed by Annexin V-FITC assay. Western immunoblotting was performed to determine the expression of the downstream targets of PI3K, MAPK and AMPK pathways. Findings: Metformin potently inhibited the proliferation of all BC cell lines in a dose-dependent manner. Likewise, metformin caused a significant dose-dependent reduction in clonogenicity of TNBC cell lines (P<0.05), but no difference was noted with regard to MCF-7. The lowest significant inhibitory concentration of metformin for MDAMB-231, HCC-70 and HCC-1937 was 1mM, 100 μM and 1mM, respectively. Of clinical relevance, the combination of metformin, at low concentration (10uM), with PTX or DOX promoted synergistic effects on the inhibition of TNBC cell viability measured by MTT (P<0.05). The combination of CDDP and metformin did not affect the viability in comparison with CDDP alone. Metformin also potentiated PTX and DOX-induced apoptosis (P<0.05). However, there was no significant increase in apoptosis with the combination of metformin and CDDP when compared with CDDP alone. In parallel, treatment of TNBC cells with metformin decreased phosphorylation of the pS6K protein, a key target of the mTOR pathway. Metformin was also found to decrease the phosphorylation of ERK1/2. Furthermore, the combination of metformin and PTX significantly inhibited the phosphorylation of ERK 1/2 and AKT compared with PTX alone in TNBC cells. Conclusions: We herein demonstrate a synergistic effect of metformin, at low and safe concentration, with PTX or DOX in suppressing human TNBC cell lines proliferation and activation of key targets in cancer therapy. Moreover, this combination is appealing because metformin is a low cost drug, with known pharmacokinetics and a favorable safety profile. Our results support the continued investigation of the addition of metformin to anthracyclines- and taxanes-based therapies against TNBC. Citation Format: Isabella S. Guimaraes, Nayara G. Tessarollo, Laura FRL Oliveira, Roger C. Zampier, Ian V. Silva, Cinthya Sternberg, Leticia BA Rangel. Metformin inhibits proliferation and acts synergistically with paclitaxel and doxorubicin in triple negative breast cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2571. doi:10.1158/1538-7445.AM2015-2571

Background: Cancer development has been associated with alterations in polyamine biosynthesis and metabolism, which induce cell proliferation, angiogenesis, expression of genes related to tumor invasion and metastasis; whereas inhibit apoptosis. Based on the strong rational to develop novel polyamine depleting molecules, and adding the strategy to have substances that can control cancer through different cellular pathways aiming to bypass the acquisition of drug resistant phenotype by cancer cells; this work aimed to screen, in an ovarian cancer (OVCA) line, 40 novel rationally developed potential anti-cancer compounds, following rapid, high efficient, and low cost synthetic methodologies, then confirmed by spectroscopic techniques. OVCA is the most lethal gynecological malignancy, with high rates of chemoresistance and disease relapse; therefore, supporting the urge to generate novel anti-OVCA agents. Methods: Novel naphthoquinone-derived compounds were rationally designed to act through multiple cellular pathways aiming the avoidance of drug resistant phenotype acquisition by cancer cells, and were synthesized by rapid, efficient and low cost synthetic method. Drugs antineoplastic efficacy (AE) was accessed in OVCAR3, through the evaluation of cellular metabolic viability (CMV) (MTT method). Drugs structures are protected by patent. Cells were cultured in RPMI media supplemented with 10% (v/v) FBS, antibiotics and antifungics, in 5% CO2, until subconfluence; then, 1.5x105 cells/well were subcultured for 72h prior to treatment with drugs in different concentrations (10−4, 10−5, 10−6, 10−7, and 10−8 M). After 24h, CMV was assessed. Experiments in which the lineage was treated with cisplatin, doxorubicin or paclitaxel were run in parallel. The mean and standard-deviation of the absorbancies were used to calculate CMV and drugs IC50 (PrismaGraphPad version 5.1). Findings: We have screened the AE of 40 novel naphtoquinone-derived drugs in OVCAR3; five have decreased its CMV by, at least, 70%, namely: M8 (IC50 1.64x10−5M; CMV decrease of 90%); M10 (IC50 1.37x10−5M; CMV decrease of 96%); M14 (IC50 1.45x10−5M; CMV decrease of 85%); PIC10 (IC50 9.13x10−6M; CMV decrease of 95%); PIC20 (IC50 5.31x10−5M; CMV decrease of 70%). The IC50 for cisplatin, the gold therapy against OVCA was 3.87x10−5M and CMV decrease was 85%. Interpretation: We herein present novel drugs to treat OVCA; whereas PIC 10 is more potent that cisplatin, M8, M10, M14, PIC10 and PIC20 seem to have similar or higher antineoplastic efficacy in treating cisplatin-resistant OVCA. We strongly believe that the present pre-clinical research project is innovative, as it introduces novel anti-OVCA drugs, economically viable and socially important, as it might bring hope to put OVCA treatment in a perspective in which the disease control is a real possibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 924. doi:1538-7445.AM2012-924