Silvia Carvalho - Academia.edu (original) (raw)
Books by Silvia Carvalho
Esta coletânea consta de nove artigos novos e republicação de seis outros, que já saíram inicialm... more Esta coletânea consta de nove artigos novos e republicação de seis outros, que já saíram inicialmente na Revista "Perspectivas" da UNESP.
Papers by Silvia Carvalho
Acta Medica Portuguesa, 2008
British Journal of Pharmacology, 2016
Antibody-based therapy of cancer employs monoclonal antibodies (mAbs) specific to soluble ligands... more Antibody-based therapy of cancer employs monoclonal antibodies (mAbs) specific to soluble ligands, membrane antigens of T-lymphocytes or proteins located at the surface of cancer cells. The latter mAbs are often combined with cytotoxic regimens, because they block survival of residual fractions of tumours that evade therapy-induced cell death. Antibodies, along with kinase inhibitors, have become in the last decade the mainstay of oncological pharmacology. However, partial and transient responses, as well as emergence of tumour resistance, currently limit clinical application of mAbs. To overcome these hurdles, oligoclonal antibody mixtures are being tested in animal models and in clinical trials. The first homo-combination of two mAbs, each engaging a distinct site of HER2, an oncogenic receptor tyrosine kinase (RTK), has been approved for treatment of breast cancer. Likewise, a hetero-combination of antibodies to two distinct T-cell antigens, PD1 and CTLA4, has been approved for treatment of melanoma. In a similar vein, additive or synergistic anti-tumour effects observed in animal models has prompted clinical testing of hetero-combinations of antibodies simultaneously engaging distinct RTKs. We discuss the promise of antibody cocktails reminiscent of currently used mixtures of chemotherapeutics, and highlight mechanisms potentially underlying their enhanced clinical efficacy. This article is protected by copyright. All rights reserved.
Eur J Org Chem, 2007
N,N-Dialkyladenine derivatives were prepared by two different reaction sequences starting from 5-... more N,N-Dialkyladenine derivatives were prepared by two different reaction sequences starting from 5-amino-4-cyanoformimidoylimidazoles. When these imidazoles were treated with dimethylformamide diethyl acetal, a 5-aminomethyleneamino-4-cyanoformimidoylimidazole was isolated and evolved to the N,N-dialkyladenine in the presence of a secondary alkylamine. The same purine structure was isolated
Virus Genes, 2010
Dengue virus (DENV; Genus Flavivirus, Family Flaviviridae) has been circulating in Brazil since a... more Dengue virus (DENV; Genus Flavivirus, Family Flaviviridae) has been circulating in Brazil since at least the mid-1980s and continues to be responsible for sporadic cases of Dengue fever and Dengue hemorrhagic fever throughout this country. Here, we describe the full genomes of two new Brazilian DENV-serotype 1 (DENV-1) variants and analyze these together with all other available American DENV-1 full-genome sequences. Besides confirming the existence of various country-specific DENV-1 founder effects that have produced a high degree of geographical structure in the American DENV-1 population, we also identify that one of the new viruses is one of only three detectable intra-American DENV-1 recombinants. Although such obvious evidence of genetic exchange among epidemiologically unlinked Latin American DENV-1 sequences is relatively rare, we find that at the population-scale there exists substantial evidence of pervasive recombination that most likely occurs between viruses that are so genetically similar that it is not possible to reliably distinguish and characterize individual recombination events.
Oncogene, 2015
Growth factors of the epidermal growth factor (EGF)/neuregulin family are involved in tumor progr... more Growth factors of the epidermal growth factor (EGF)/neuregulin family are involved in tumor progression and, accordingly, antibodies that intercept a cognate receptor, epidermal growth factor receptor (EGFR)/ERBB1, or a co-receptor, HER2, have been approved for cancer therapy. Although they might improve safety and delay onset of chemoresistance, no anti-ligand antibodies have been clinically approved. To identify suitable ligands, we surveyed fluids from ovarian and lung cancer patients and found that amphiregulin (AREG) is the most abundant and generalized ligand secreted by advanced tumors. AREG is a low affinity EGFR ligand, which is upregulated following treatment with chemotherapeutic drugs. Because AREG depletion retarded growth of xenografted ovarian tumors in mice, we generated a neutralizing monoclonal anti-AREG antibody. The antibody inhibited growth of ovarian cancer xenografts and strongly enhanced chemotherapy efficacy. Taken together, these results raise the possibility that AREG and other low- or high-affinity binders of EGFR might serve as potential targets for cancer therapy.Oncogene advance online publication, 27 April 2015; doi:10.1038/onc.2015.93.
Nature cell biology, Jan 6, 2015
The murine neonatal heart can regenerate after injury through cardiomyocyte (CM) proliferation, a... more The murine neonatal heart can regenerate after injury through cardiomyocyte (CM) proliferation, although this capacity markedly diminishes after the first week of life. Neuregulin-1 (NRG1) administration has been proposed as a strategy to promote cardiac regeneration. Here, using loss- and gain-of-function genetic tools, we explore the role of the NRG1 co-receptor ERBB2 in cardiac regeneration. NRG1-induced CM proliferation diminished one week after birth owing to a reduction in ERBB2 expression. CM-specific Erbb2 knockout revealed that ERBB2 is required for CM proliferation at embryonic/neonatal stages. Induction of a constitutively active ERBB2 (caERBB2) in neonatal, juvenile and adult CMs resulted in cardiomegaly, characterized by extensive CM hypertrophy, dedifferentiation and proliferation, differentially mediated by ERK, AKT and GSK3β/β-catenin signalling pathways. Transient induction of caERBB2 following myocardial infarction triggered CM dedifferentiation and proliferation f...
Science signaling, Jan 17, 2015
Growth factors promote tumor growth and metastasis. We found that epidermal growth factor (EGF) i... more Growth factors promote tumor growth and metastasis. We found that epidermal growth factor (EGF) induced a set of 22 microRNAs (miRNAs) before promoting the migration of mammary cells. These miRNAs were more abundant in human breast tumors relative to the surrounding tissue, and their abundance varied among breast cancer subtypes. One of these miRNAs, miR-15b, targeted the 3' untranslated region of MTSS1 (metastasis suppressor protein 1). Although xenografts in which MTSS1 was knocked down grew more slowly in mice initially, longer-term growth was unaffected. Knocking down MTSS1 increased migration and Matrigel invasion of nontransformed mammary epithelial cells. Overexpressing MTSS1 in an invasive cell line decreased cell migration and invasiveness, decreased the formation of invadopodia and actin stress fibers, and increased the formation of cellular junctions. In tissues from breast cancer patients with the aggressive basal subtype, an inverse correlation occurred with the hig...
EMBO Molecular Medicine, 2015
Dissemination of primary tumor cells depends on migratory and invasive attributes. Here, we ident... more Dissemination of primary tumor cells depends on migratory and invasive attributes. Here, we identify Navigator-3 (NAV3), a gene frequently mutated or deleted in human tumors, as a regulator of epithelial migration and invasion. Following induction by growth factors, NAV3 localizes to the plus ends of microtubules and enhances their polarized growth. Accordingly, NAV3 depletion trimmed microtubule growth, prolonged growth factor signaling, prevented apoptosis and enhanced random cell migration. Mathematical modeling suggested that NAV3-depleted cells acquire an advantage in terms of the way they explore their environment. In animal models, silencing NAV3 increased metastasis, whereas ectopic expression of the wild-type form, unlike expression of two, relatively unstable oncogenic mutants from human tumors, inhibited metastasis. Congruently, analyses of > 2,500 breast and lung cancer patients associated low NAV3 with shorter survival. We propose that NAV3 inhibits breast cancer progression by regulating microtubule dynamics, biasing directionally persistent rather than random migration, and inhibiting locomotion of initiated cells.
Lecture Notes in Computer Science, 2004
Data mining applications are composed of computing-intensive processing tasks, which are natural ... more Data mining applications are composed of computing-intensive processing tasks, which are natural candidates for execution on high performance, high throughput platforms such as PC clusters and computational grids. Besides, some data-mining algorithms can be implemented as Bag-of-Tasks (BoT) applications, which are composed of parallel, independent tasks. Due to its own nature, the adaptation of BoT applications for the grid is straightforward. In this sense, this work proposes a scheduling algorithm for running BoT data mining applications on grid platforms. The proposed algorithm is evaluated by means of several experiments, and the obtained results show that it improves both scalability and performance of such applications.
Gastric Cancer, 2014
Gastric cancer represents one of the most common causes of cancer deaths worldwide. Overexpressio... more Gastric cancer represents one of the most common causes of cancer deaths worldwide. Overexpression of ErbB2, a tyrosine kinase receptor involved in the pathogenesis of several human cancer types, has been reported also in gastric cancer. Thus, the inhibition of ErbB2 signal transduction pathways by the use of human antibodies could be a valuable strategy for the therapy of this type of cancer. We tested for the first time the antitumor effects on gastric cancer cells of Erb-hcAb, a novel fully human compact antibody, prepared in our laboratory, which targets a different epitope of ErbB2 with respect to trastuzumab, the only anti-ErbB2 antibody currently in clinical use for both breast and gastric cancer therapy. Herein we demonstrate that the in vitro and in vivo growth of gastric cancer cells is efficiently inhibited by Erb-hcAb, which shows antitumor effects on the NCI-N87 cell line more potent than those observed for trastuzumab. Erb-hcAb could be a promising candidate in the immunotherapy of gastric cancer as it combines the antiproliferative effect associated with the inhibition of ErbB2 signaling on tumor target cells with the ability to induce antibody-dependent cellular cytotoxicity.
Lecture Notes in Computer Science, 2004
Data mining (DM) applications are composed of computing-intensive processing tasks working on hug... more Data mining (DM) applications are composed of computing-intensive processing tasks working on huge datasets. Due to its computing-intensive nature, these applications are natural candidates for execution on high performance, high throughput platforms such as ...
![Research paper thumbnail of [Basal-like carcinoma of the breast]](https://attachments.academia-assets.com/44039436/thumbnails/1.jpg)
](Acta médica portuguesa
Breast cancer presents as a heterogeneous disease, not only for the clinic and histology, but als... more Breast cancer presents as a heterogeneous disease, not only for the clinic and histology, but also in genetic expression profile. Studies using cDNA microarrays have recently led to the re-classification of invasive breast carcinomas, based on their molecular signature, into three main groups: luminal; HER2 (Human Epidermal Receptor 2) overexpressing, and basal-like. Although the latter group is the least prevalent it is the most aggressive one, lacking a target based therapy, since their main characteristic is being negative for hormonal receptors or HER2. So, it is of paramount importance to try to unravel their histogenic origin and characterize their molecular and immunohistochemical profiles. EGFR (Epidermal Growth Factor Receptor), which is overexpressed in a high proportion of these carcinomas, is a potential therapeutic target, and clinical trials with inhibitors of its activity may represent important advances in basal-like breast carcinomas therapy.
Breast cancer research : BCR, 2005
Metaplastic breast carcinomas constitute a heterogeneous group of neoplasms, accounting for less ... more Metaplastic breast carcinomas constitute a heterogeneous group of neoplasms, accounting for less than 1% of all invasive mammary carcinomas. Approximately 70-80% of metaplastic breast carcinomas overexpress the epidermal growth factor receptor (EGFR). Human epidermal growth factor receptor (HER)2 and EGFR have attracted much attention in the medical literature over the past few years owing to the fact that humanized monoclonal antibodies against HER2 and therapies directed against the extracellular ligand-binding domain or the intracellular tyrosine kinase domain of EGFR have proven successful in treating certain types of human cancer. We investigated whether HER2 and EGFR overexpression was present and evaluated gene amplification in a series of metaplastic breast carcinomas. Twenty-five metaplastic breast carcinomas were immunohistochemically analyzed using a monoclonal antibody (31G7) for EGFR and two antibodies for HER2 (Herceptest and CB11) and scored using the Herceptest scori...
Science Signaling, 2015
Amplified HER2, which encodes a member of the epidermal growth factor receptor (EGFR) family, is ... more Amplified HER2, which encodes a member of the epidermal growth factor receptor (EGFR) family, is a target of effective therapies against breast cancer. In search for similarly targetable genomic aberrations, we identified copy number gains in SYNJ2, which encodes the 5′-inositol lipid phosphatase synaptojanin 2, as well as overexpression in a small fraction of human breast tumors. Copy gain and overexpression correlated with shorter patient survival and a low abundance of the tumor suppressor microRNA miR-31. SYNJ2 promoted cell migration and invasion in culture and lung metastasis of breast tumor xenografts in mice. Knocking down SYNJ2 impaired the endocytic recycling of EGFR and the formation of cellular lamellipodia and invadopodia. Screening compound libraries identified SYNJ2-specific inhibitors that prevented cell migration but did not affect the related neural protein SYNJ1, suggesting that SYNJ2 is a potentially druggable target to block cancer cell migration.
Nature Communications, 2014
Signal transduction by receptor tyrosine kinases (RTKs) and nuclear receptors for steroid hormone... more Signal transduction by receptor tyrosine kinases (RTKs) and nuclear receptors for steroid hormones is essential for body homeostasis, but the cross-talk between these receptor families is poorly understood. We observed that glucocorticoids inhibit signalling downstream of EGFR, an RTK. The underlying mechanism entails suppression of EGFR's positive feedback loops and simultaneous triggering of negative feedback loops that normally restrain EGFR. Our studies in mice reveal that the regulation of EGFR's feedback loops by glucocorticoids translates to circadian control of EGFR signalling: EGFR signals are suppressed by high glucocorticoids during the active phase (night-time in rodents), while EGFR signals are enhanced during the resting phase. Consistent with this pattern, treatment of animals bearing EGFR-driven tumours with a specific kinase inhibitor was more effective if administered during the resting phase of the day, when glucocorticoids are low. These findings support a circadian clock-based paradigm in cancer therapy.
Virchows Archiv, 2010
Class IA phosphoinositide-3&a... more Class IA phosphoinositide-3'-kinases (PI3Ks) regulate many cellular processes. Despite a clear implication of PI3K in cancer, the involvement of each of its isoforms namely p110alpha and p110beta in the development of breast cancer remains elusive. Until recently, the spotlight was given to the alpha subunit; however, the p110beta isoform has now emerged as an interesting target as well. In order to determine the importance of both these subunits in breast cancer, we aimed to study the expression of p110alpha and p110beta in a series of invasive breast carcinomas. We constructed tissue microarrays from 315 invasive breast carcinomas and performed immunohistochemistry for p110alpha and beta, correlating the expression patterns with clinicopathological parameters. Furthermore, overall survival was analysed through Kaplan-Meier survival curves and Cox regression. We found that p110 subunits are expressed in 23.8% of invasive breast carcinomas, of which 11.8% express p110alpha and 15.2% p110beta. The p110alpha positive tumours correlated with hormone receptor (HR) expression, and were not associated with overall survival. The membrane expression of p110beta was associated with worse prognosis. This was due to its link to HER2-overexpression, lower age of onset, higher grade, lymph node involvement, distant metastasis and was inversely associated with HR status. Furthermore, p110beta expression was associated with worse overall survival. Importantly our results indicate a role for the beta subunit in the development/progression of HER2-overexpressing tumours, highlighting possible therapeutic associations between HER2 and p110beta inhibitors.
Esta coletânea consta de nove artigos novos e republicação de seis outros, que já saíram inicialm... more Esta coletânea consta de nove artigos novos e republicação de seis outros, que já saíram inicialmente na Revista "Perspectivas" da UNESP.
Acta Medica Portuguesa, 2008
British Journal of Pharmacology, 2016
Antibody-based therapy of cancer employs monoclonal antibodies (mAbs) specific to soluble ligands... more Antibody-based therapy of cancer employs monoclonal antibodies (mAbs) specific to soluble ligands, membrane antigens of T-lymphocytes or proteins located at the surface of cancer cells. The latter mAbs are often combined with cytotoxic regimens, because they block survival of residual fractions of tumours that evade therapy-induced cell death. Antibodies, along with kinase inhibitors, have become in the last decade the mainstay of oncological pharmacology. However, partial and transient responses, as well as emergence of tumour resistance, currently limit clinical application of mAbs. To overcome these hurdles, oligoclonal antibody mixtures are being tested in animal models and in clinical trials. The first homo-combination of two mAbs, each engaging a distinct site of HER2, an oncogenic receptor tyrosine kinase (RTK), has been approved for treatment of breast cancer. Likewise, a hetero-combination of antibodies to two distinct T-cell antigens, PD1 and CTLA4, has been approved for treatment of melanoma. In a similar vein, additive or synergistic anti-tumour effects observed in animal models has prompted clinical testing of hetero-combinations of antibodies simultaneously engaging distinct RTKs. We discuss the promise of antibody cocktails reminiscent of currently used mixtures of chemotherapeutics, and highlight mechanisms potentially underlying their enhanced clinical efficacy. This article is protected by copyright. All rights reserved.
Eur J Org Chem, 2007
N,N-Dialkyladenine derivatives were prepared by two different reaction sequences starting from 5-... more N,N-Dialkyladenine derivatives were prepared by two different reaction sequences starting from 5-amino-4-cyanoformimidoylimidazoles. When these imidazoles were treated with dimethylformamide diethyl acetal, a 5-aminomethyleneamino-4-cyanoformimidoylimidazole was isolated and evolved to the N,N-dialkyladenine in the presence of a secondary alkylamine. The same purine structure was isolated
Virus Genes, 2010
Dengue virus (DENV; Genus Flavivirus, Family Flaviviridae) has been circulating in Brazil since a... more Dengue virus (DENV; Genus Flavivirus, Family Flaviviridae) has been circulating in Brazil since at least the mid-1980s and continues to be responsible for sporadic cases of Dengue fever and Dengue hemorrhagic fever throughout this country. Here, we describe the full genomes of two new Brazilian DENV-serotype 1 (DENV-1) variants and analyze these together with all other available American DENV-1 full-genome sequences. Besides confirming the existence of various country-specific DENV-1 founder effects that have produced a high degree of geographical structure in the American DENV-1 population, we also identify that one of the new viruses is one of only three detectable intra-American DENV-1 recombinants. Although such obvious evidence of genetic exchange among epidemiologically unlinked Latin American DENV-1 sequences is relatively rare, we find that at the population-scale there exists substantial evidence of pervasive recombination that most likely occurs between viruses that are so genetically similar that it is not possible to reliably distinguish and characterize individual recombination events.
Oncogene, 2015
Growth factors of the epidermal growth factor (EGF)/neuregulin family are involved in tumor progr... more Growth factors of the epidermal growth factor (EGF)/neuregulin family are involved in tumor progression and, accordingly, antibodies that intercept a cognate receptor, epidermal growth factor receptor (EGFR)/ERBB1, or a co-receptor, HER2, have been approved for cancer therapy. Although they might improve safety and delay onset of chemoresistance, no anti-ligand antibodies have been clinically approved. To identify suitable ligands, we surveyed fluids from ovarian and lung cancer patients and found that amphiregulin (AREG) is the most abundant and generalized ligand secreted by advanced tumors. AREG is a low affinity EGFR ligand, which is upregulated following treatment with chemotherapeutic drugs. Because AREG depletion retarded growth of xenografted ovarian tumors in mice, we generated a neutralizing monoclonal anti-AREG antibody. The antibody inhibited growth of ovarian cancer xenografts and strongly enhanced chemotherapy efficacy. Taken together, these results raise the possibility that AREG and other low- or high-affinity binders of EGFR might serve as potential targets for cancer therapy.Oncogene advance online publication, 27 April 2015; doi:10.1038/onc.2015.93.
Nature cell biology, Jan 6, 2015
The murine neonatal heart can regenerate after injury through cardiomyocyte (CM) proliferation, a... more The murine neonatal heart can regenerate after injury through cardiomyocyte (CM) proliferation, although this capacity markedly diminishes after the first week of life. Neuregulin-1 (NRG1) administration has been proposed as a strategy to promote cardiac regeneration. Here, using loss- and gain-of-function genetic tools, we explore the role of the NRG1 co-receptor ERBB2 in cardiac regeneration. NRG1-induced CM proliferation diminished one week after birth owing to a reduction in ERBB2 expression. CM-specific Erbb2 knockout revealed that ERBB2 is required for CM proliferation at embryonic/neonatal stages. Induction of a constitutively active ERBB2 (caERBB2) in neonatal, juvenile and adult CMs resulted in cardiomegaly, characterized by extensive CM hypertrophy, dedifferentiation and proliferation, differentially mediated by ERK, AKT and GSK3β/β-catenin signalling pathways. Transient induction of caERBB2 following myocardial infarction triggered CM dedifferentiation and proliferation f...
Science signaling, Jan 17, 2015
Growth factors promote tumor growth and metastasis. We found that epidermal growth factor (EGF) i... more Growth factors promote tumor growth and metastasis. We found that epidermal growth factor (EGF) induced a set of 22 microRNAs (miRNAs) before promoting the migration of mammary cells. These miRNAs were more abundant in human breast tumors relative to the surrounding tissue, and their abundance varied among breast cancer subtypes. One of these miRNAs, miR-15b, targeted the 3' untranslated region of MTSS1 (metastasis suppressor protein 1). Although xenografts in which MTSS1 was knocked down grew more slowly in mice initially, longer-term growth was unaffected. Knocking down MTSS1 increased migration and Matrigel invasion of nontransformed mammary epithelial cells. Overexpressing MTSS1 in an invasive cell line decreased cell migration and invasiveness, decreased the formation of invadopodia and actin stress fibers, and increased the formation of cellular junctions. In tissues from breast cancer patients with the aggressive basal subtype, an inverse correlation occurred with the hig...
EMBO Molecular Medicine, 2015
Dissemination of primary tumor cells depends on migratory and invasive attributes. Here, we ident... more Dissemination of primary tumor cells depends on migratory and invasive attributes. Here, we identify Navigator-3 (NAV3), a gene frequently mutated or deleted in human tumors, as a regulator of epithelial migration and invasion. Following induction by growth factors, NAV3 localizes to the plus ends of microtubules and enhances their polarized growth. Accordingly, NAV3 depletion trimmed microtubule growth, prolonged growth factor signaling, prevented apoptosis and enhanced random cell migration. Mathematical modeling suggested that NAV3-depleted cells acquire an advantage in terms of the way they explore their environment. In animal models, silencing NAV3 increased metastasis, whereas ectopic expression of the wild-type form, unlike expression of two, relatively unstable oncogenic mutants from human tumors, inhibited metastasis. Congruently, analyses of > 2,500 breast and lung cancer patients associated low NAV3 with shorter survival. We propose that NAV3 inhibits breast cancer progression by regulating microtubule dynamics, biasing directionally persistent rather than random migration, and inhibiting locomotion of initiated cells.
Lecture Notes in Computer Science, 2004
Data mining applications are composed of computing-intensive processing tasks, which are natural ... more Data mining applications are composed of computing-intensive processing tasks, which are natural candidates for execution on high performance, high throughput platforms such as PC clusters and computational grids. Besides, some data-mining algorithms can be implemented as Bag-of-Tasks (BoT) applications, which are composed of parallel, independent tasks. Due to its own nature, the adaptation of BoT applications for the grid is straightforward. In this sense, this work proposes a scheduling algorithm for running BoT data mining applications on grid platforms. The proposed algorithm is evaluated by means of several experiments, and the obtained results show that it improves both scalability and performance of such applications.
Gastric Cancer, 2014
Gastric cancer represents one of the most common causes of cancer deaths worldwide. Overexpressio... more Gastric cancer represents one of the most common causes of cancer deaths worldwide. Overexpression of ErbB2, a tyrosine kinase receptor involved in the pathogenesis of several human cancer types, has been reported also in gastric cancer. Thus, the inhibition of ErbB2 signal transduction pathways by the use of human antibodies could be a valuable strategy for the therapy of this type of cancer. We tested for the first time the antitumor effects on gastric cancer cells of Erb-hcAb, a novel fully human compact antibody, prepared in our laboratory, which targets a different epitope of ErbB2 with respect to trastuzumab, the only anti-ErbB2 antibody currently in clinical use for both breast and gastric cancer therapy. Herein we demonstrate that the in vitro and in vivo growth of gastric cancer cells is efficiently inhibited by Erb-hcAb, which shows antitumor effects on the NCI-N87 cell line more potent than those observed for trastuzumab. Erb-hcAb could be a promising candidate in the immunotherapy of gastric cancer as it combines the antiproliferative effect associated with the inhibition of ErbB2 signaling on tumor target cells with the ability to induce antibody-dependent cellular cytotoxicity.
Lecture Notes in Computer Science, 2004
Data mining (DM) applications are composed of computing-intensive processing tasks working on hug... more Data mining (DM) applications are composed of computing-intensive processing tasks working on huge datasets. Due to its computing-intensive nature, these applications are natural candidates for execution on high performance, high throughput platforms such as ...
Acta médica portuguesa
Breast cancer presents as a heterogeneous disease, not only for the clinic and histology, but als... more Breast cancer presents as a heterogeneous disease, not only for the clinic and histology, but also in genetic expression profile. Studies using cDNA microarrays have recently led to the re-classification of invasive breast carcinomas, based on their molecular signature, into three main groups: luminal; HER2 (Human Epidermal Receptor 2) overexpressing, and basal-like. Although the latter group is the least prevalent it is the most aggressive one, lacking a target based therapy, since their main characteristic is being negative for hormonal receptors or HER2. So, it is of paramount importance to try to unravel their histogenic origin and characterize their molecular and immunohistochemical profiles. EGFR (Epidermal Growth Factor Receptor), which is overexpressed in a high proportion of these carcinomas, is a potential therapeutic target, and clinical trials with inhibitors of its activity may represent important advances in basal-like breast carcinomas therapy.
Breast cancer research : BCR, 2005
Metaplastic breast carcinomas constitute a heterogeneous group of neoplasms, accounting for less ... more Metaplastic breast carcinomas constitute a heterogeneous group of neoplasms, accounting for less than 1% of all invasive mammary carcinomas. Approximately 70-80% of metaplastic breast carcinomas overexpress the epidermal growth factor receptor (EGFR). Human epidermal growth factor receptor (HER)2 and EGFR have attracted much attention in the medical literature over the past few years owing to the fact that humanized monoclonal antibodies against HER2 and therapies directed against the extracellular ligand-binding domain or the intracellular tyrosine kinase domain of EGFR have proven successful in treating certain types of human cancer. We investigated whether HER2 and EGFR overexpression was present and evaluated gene amplification in a series of metaplastic breast carcinomas. Twenty-five metaplastic breast carcinomas were immunohistochemically analyzed using a monoclonal antibody (31G7) for EGFR and two antibodies for HER2 (Herceptest and CB11) and scored using the Herceptest scori...
Science Signaling, 2015
Amplified HER2, which encodes a member of the epidermal growth factor receptor (EGFR) family, is ... more Amplified HER2, which encodes a member of the epidermal growth factor receptor (EGFR) family, is a target of effective therapies against breast cancer. In search for similarly targetable genomic aberrations, we identified copy number gains in SYNJ2, which encodes the 5′-inositol lipid phosphatase synaptojanin 2, as well as overexpression in a small fraction of human breast tumors. Copy gain and overexpression correlated with shorter patient survival and a low abundance of the tumor suppressor microRNA miR-31. SYNJ2 promoted cell migration and invasion in culture and lung metastasis of breast tumor xenografts in mice. Knocking down SYNJ2 impaired the endocytic recycling of EGFR and the formation of cellular lamellipodia and invadopodia. Screening compound libraries identified SYNJ2-specific inhibitors that prevented cell migration but did not affect the related neural protein SYNJ1, suggesting that SYNJ2 is a potentially druggable target to block cancer cell migration.
Nature Communications, 2014
Signal transduction by receptor tyrosine kinases (RTKs) and nuclear receptors for steroid hormone... more Signal transduction by receptor tyrosine kinases (RTKs) and nuclear receptors for steroid hormones is essential for body homeostasis, but the cross-talk between these receptor families is poorly understood. We observed that glucocorticoids inhibit signalling downstream of EGFR, an RTK. The underlying mechanism entails suppression of EGFR's positive feedback loops and simultaneous triggering of negative feedback loops that normally restrain EGFR. Our studies in mice reveal that the regulation of EGFR's feedback loops by glucocorticoids translates to circadian control of EGFR signalling: EGFR signals are suppressed by high glucocorticoids during the active phase (night-time in rodents), while EGFR signals are enhanced during the resting phase. Consistent with this pattern, treatment of animals bearing EGFR-driven tumours with a specific kinase inhibitor was more effective if administered during the resting phase of the day, when glucocorticoids are low. These findings support a circadian clock-based paradigm in cancer therapy.
Virchows Archiv, 2010
Class IA phosphoinositide-3&a... more Class IA phosphoinositide-3'-kinases (PI3Ks) regulate many cellular processes. Despite a clear implication of PI3K in cancer, the involvement of each of its isoforms namely p110alpha and p110beta in the development of breast cancer remains elusive. Until recently, the spotlight was given to the alpha subunit; however, the p110beta isoform has now emerged as an interesting target as well. In order to determine the importance of both these subunits in breast cancer, we aimed to study the expression of p110alpha and p110beta in a series of invasive breast carcinomas. We constructed tissue microarrays from 315 invasive breast carcinomas and performed immunohistochemistry for p110alpha and beta, correlating the expression patterns with clinicopathological parameters. Furthermore, overall survival was analysed through Kaplan-Meier survival curves and Cox regression. We found that p110 subunits are expressed in 23.8% of invasive breast carcinomas, of which 11.8% express p110alpha and 15.2% p110beta. The p110alpha positive tumours correlated with hormone receptor (HR) expression, and were not associated with overall survival. The membrane expression of p110beta was associated with worse prognosis. This was due to its link to HER2-overexpression, lower age of onset, higher grade, lymph node involvement, distant metastasis and was inversely associated with HR status. Furthermore, p110beta expression was associated with worse overall survival. Importantly our results indicate a role for the beta subunit in the development/progression of HER2-overexpressing tumours, highlighting possible therapeutic associations between HER2 and p110beta inhibitors.
Science, 2009
ABSTRACT Conservation performance in securing biodiversity can be evaluated better with metrics b... more ABSTRACT Conservation performance in securing biodiversity can be evaluated better with metrics based on the concept of a conservation balance sheet.