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Breast cancer (BCa) is a complex and heterogeneous disease, with different intrinsic molecular subtypes that have distinct clinical outcomes and responses to therapy. Although intrinsic subtyping provides guidance for treatment decisions, it is now widely recognised that, in some cases, the switch of the BCa intrinsic subtype (which embodies cellular plasticity), may be responsible for therapy failure and disease progression. Aberrant FGFR4 signalling has been implicated in various cancers, including BCa, where it had been shown to be associated with aggressive subtypes, such as HER2-enriched BCa, and poor prognosis. More importantly, FGFR4 is also emerging as a potential driver of BCa intrinsic subtype switching, and an essential promoter of brain metastases, particularly in the HER2-positive BCa. Although the available data are still limited, the findings may have far-reaching clinical implications. Here, we provide an updated summary of the existing both pre- and clinical studies of the role of FGFR4 in BCa, with a special focus on its contribution to subtype switching during metastatic spread and/or induced by therapy. We also discuss a potential clinical benefit of targeting FGFR4 in the development of new treatment strategies.
Assuntos
Neoplasias da Mama , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos , Humanos , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Feminino , Transdução de SinaisRESUMO
BACKGROUND: Genetic abnormalities in the FGFR signalling occur in 40% of breast cancer (BCa) patients resistant to anti-ER therapy, which emphasizes the potential of FGFR-targeting strategies. Recent findings indicate that not only mutated FGFR is a driver of tumour progression but co-mutational landscapes and other markers should be also investigated. Autophagy has been recognized as one of the major mechanisms underlying the role of tumour microenvironment in promotion of cancer cell survival, and resistance to anti-ER drugs. The selective autophagy receptor p62/SQSTM1 promotes Nrf-2 activation by Keap1/Nrf-2 complex dissociation. Herein, we have analysed whether the negative effect of FGFR2 on BCa cell response to anti-ER treatment involves the autophagy process and/or p62/Keap1/Nrf-2 axis. METHODS: The activity of autophagy in ER-positive MCF7 and T47D BCa cell lines was determined by analysis of expression level of autophagy markers (p62 and LC3B) and monitoring of autophagosomes' maturation. Western blot, qPCR and proximity ligation assay were used to determine the Keap1/Nrf-2 interaction and Nrf-2 activation. Analysis of 3D cell growth in Matrigel® was used to assess BCa cell response to applied treatments. In silico gene expression analysis was performed to determine FGFR2/Nrf-2 prognostic value. RESULTS: We have found that FGFR2 signalling induced autophagy in AMPKα/ULK1-dependent manner. FGFR2 activity promoted dissociation of Keap1/Nrf-2 complex and activation of Nrf-2. Both, FGFR2-dependent autophagy and activation of Nrf-2 were found to counteract the effect of anti-ER drugs on BCa cell growth. Moreover, in silico analysis showed that high expression of NFE2L2 (gene encoding Nrf-2) combined with high FGFR2 expression was associated with poor relapse-free survival (RFS) of ER+ BCa patients. CONCLUSIONS: This study revealed the unknown role of FGFR2 signalling in activation of autophagy and regulation of the p62/Keap1/Nrf-2 interdependence, which has a negative impact on the response of ER+ BCa cells to anti-ER therapies. The data from in silico analyses suggest that expression of Nrf-2 could act as a marker indicating potential benefits of implementation of anti-FGFR therapy in patients with ER+ BCa, in particular, when used in combination with anti-ER drugs.
Assuntos
Autofagia , Neoplasias da Mama , Proteína 1 Associada a ECH Semelhante a Kelch , Fator 2 Relacionado a NF-E2 , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Feminino , Humanos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Células MCF-7 , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Proteína Sequestossoma-1/metabolismo , Proteína Sequestossoma-1/genética , Transdução de Sinais/efeitos dos fármacos , Antagonistas de Estrogênios/farmacologia , Moduladores de Receptor Estrogênico/farmacologiaRESUMO
Gastrointestinal neoplasms most commonly metastasize to the liver, where they are typically found as solid and hypervascular lesions. Here, we describe a case of a 44-year-old man with a leiomyosarcoma of the rectum, who at the time of diagnosis presented with a small (5 mm in diameter) cyst-like lesion in the liver. Positron emission tomography demonstrated no increased metabolism in the area of the cyst, suggesting a benign character of the lesion. However, after 3 years, CT scans revealed enlargement of the cyst, and local surgical excision was performed. The results of histopathological examination of the resected material were consistent with metastatic leiomyosarcoma. Subsequently, the patient developed lung metastases and died within 2 years. Our case describes a very rare presentation of leiomyosarcoma's metastasis that led to an ill-fated misdiagnosis and dismal disease outcome.
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Pulmonary tumour embolism is a rare condition without specific symptoms or pathognomonic features. Pulmonary tumour embolism can occur as the first manifestation of cancer, but because of diagnostic difficulties, it is often wrongly recognised as a more common cardiopulmonary disease. We present a case of a 46-year-old Caucasian male with no prior malignancy diagnosis, admitted because of progressing dyspnoea and cough. Based on radiological and clinical presentations, sarcoidosis, silicosis and lymphangitic carcinomatosis were considered in the differential diagnosis. Histopathological analysis of lung biopsy revealed that multiple emboli of atypical epithelial cells found in the pulmonary vessels were of gastrointestinal origin. Further pathological examination of the gastric biopsy led to the final diagnosis of the signet-ring cells gastric adenocarcinoma. The patient was referred for chemotherapy. After a short-term partial remission, he died within two months after the final diagnosis. The presented case illustrates challenges posed by the diagnostic process of pulmonary tumour embolism.
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Adenoid cystic carcinoma (AdCC) is a common tumour of the minor salivary gland, rarely seen in other anatomical locations. In particular, AdCC of the breast accounts for < 0.1% of patients diagnosed with breast cancer. Here we report our institutional experience with three cases of breast AdCC diagnosed between 2009 and 2017. Mean age of women included in the report was 53 (range from 41 to 62). One case was of no special subtype, two were solid variants and one presented with a component of invasive ductal carcinoma. At diagnosis in all cases neither lymph node involvement nor distal metastases were detected. All patients underwent surgical resection of the tumour - mastectomy or lumpectomy, followed by either adjuvant radiotherapy and chemotherapy (one case), chemotherapy without radiotherapy (one case) or no treatment (one case). Two patients were reported to develop metastatic disease. No deaths were recorded. In contrast to other anatomical locations AdCC of the breast is regarded as a rare tumour with low malignant potential. However, as shown in our case series, it can present as an aggressive disease with distal metastases, which calls for deep awareness among both pathologists and clinicians involved in the process of diagnosis and therapy.
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The tetraspanins are a superfamily of four-transmembrane proteins, which regulate the trafficking, lateral diffusion and clustering of the transmembrane proteins with which they interact. We have previously shown that tetraspanin Tspan9 is expressed on platelets. Here we have characterised gene-trap mice lacking Tspan9. The mice were viable with normal platelet numbers and size. Tspan9-deficient platelets were specifically defective in aggregation and secretion induced by the platelet collagen receptor GPVI, despite normal surface GPVI expression levels. A GPVI activation defect was suggested by partially impaired GPVI-induced protein tyrosine phosphorylation. In mechanistic experiments, Tspan9 and GPVI co-immunoprecipitated and co-localised, but super-resolution imaging revealed no defects in collagen-induced GPVI clustering on Tspan9-deficient platelets. However, single particle tracking using total internal reflection fluorescence microscopy showed that GPVI lateral diffusion was reduced by approximately 50% in the absence of Tspan9. Therefore, Tspan9 plays a fine-tuning role in platelet activation by regulating GPVI membrane dynamics.
Assuntos
Plaquetas/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Glicoproteínas da Membrana de Plaquetas/genética , Tetraspaninas/genética , Difosfato de Adenosina/farmacologia , Animais , Ácido Araquidônico/farmacologia , Plaquetas/patologia , Proteínas de Transporte/farmacologia , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptídeos/farmacologia , Fosforilação , Agregação Plaquetária/efeitos dos fármacos , Glicoproteínas da Membrana de Plaquetas/metabolismo , Cultura Primária de Células , Ligação Proteica , Transporte Proteico , Transdução de Sinais , Tetraspaninas/química , Tetraspaninas/deficiênciaRESUMO
We have previously demonstrated that fibroblast growth factor receptor 2 (FGFR2) activates ribosomal s6 kinase 2 (RSK2) in mammary epithelial cells and that this pathway promotes in vitro cell growth and migration. Potential clinical significance of FGFR2 and RSK2 association has never been investigated. Herein, we have undertaken an evaluation of a possible relationship between FGFR2/RSK2 interdependence and disease outcome in breast cancer (BCa) patients. The clinical analysis was complemented by an in vitro investigation of an involvement of RSK2 in the regulation of FGFR2 function. Primary tumour samples from 152 stage I-III BCa patients were examined for FGFR2 and RSK2 gene and protein expression. FGFR2 showed a positive correlation with RSK2 at both protein (p = 0.003) and messenger RNA (mRNA) (p = 0.001) levels. Lack of both FGFR2 and activated RSK (RSK-P) significantly correlated with better disease-free survival (DFS) (p = 0.01). Patients with tumours displaying immunoreactivity for either or both FGFR2 and RSK-P had 4.89-fold higher risk of recurrence when compared to the FGFR2/RSK-P-negative subgroup. FGFR2-RSK2 interactions were verified by co-immunoprecipitation and internalization assays in HB2 mammary epithelial cell line (characterized by high endogenous FGFR2 and RSK2 expression). In vitro analyses revealed that FGFR2 and RSK2 formed an indirect complex and that activated RSK exerted a significant impact on fibroblast growth factor 2 (FGF2)-triggered internalization of FGFR2. Our results suggest that the FGFR2-RSK2 signalling pathway is involved in pathophysiology of BCa and evaluation of FGFR2/RSK-P expression may be useful in disease prognostication.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Western Blotting , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Feminino , Imunofluorescência , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
The members of p90 ribosomal S6 kinase (RSK) family of Ser/Thr kinases are downstream effectors of MAPK/ERK pathway that regulate diverse cellular processes including cell growth, proliferation and survival. In carcinogenesis, RSKs are thought to modulate cell motility, invasion and metastasis. Herein, we have studied an involvement of RSKs in FGF2/FGFR2-driven behaviours of mammary epithelial and breast cancer cells. We found that both silencing and inhibiting of FGFR2 attenuated phosphorylation of RSKs, whereas FGFR2 overexpression and/or its stimulation with FGF2 enhanced RSKs activity. Moreover, treatment with ERK, Src and p38 inhibitors revealed that p38 kinase acts as an upstream RSK2 regulator. We demonstrate for the first time that in FGF2/FGFR2 signalling, p38 but not MEK/ERK, indirectly activated RSK2 at Tyr529, which facilitated phosphorylation of its other residues (Thr359/Ser363, Thr573 and Ser380). In contrast to FGF2-triggered signalling, inhibition of p38 in the EGF pathway affected only RSK2-Tyr529, without any impact on the remaining RSK phosphorylation sites. p38-mediated phosphorylation of RSK2-Tyr529 was crucial for the transactivation of residues located at kinase C-terminal domain and linker-region, specifically, in the FGF2/FGFR2 signalling pathway. Furthermore, we show that FGF2 promoted anchorage-independent cell proliferation, formation of focal adhesions and cell migration, which was effectively abolished by treatment with RSKs inhibitor (FMK). These indicate that RSK2 activity is indispensable for FGF2/FGFR2-mediated cellular effects. Our findings identified a new FGF2/FGFR2-p38-RSK2 pathway, which may play a significant role in the pathogenesis and progression of breast cancer and, hence, may present a novel therapeutic target in the treatment of FGFR2-expressing tumours.
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BACKGROUND: The proposed involvement of CD151 in breast cancer (BCa) progression is based on findings from studies in invasive ductal carcinoma (IDC). The IDC and invasive lobular carcinoma (ILC) represent distinct disease entities. Here we evaluated clinical significance of CD151 alone and in association with integrin α3ß1 in patients with ILC in context of the data of our recent IDC study. METHODS: Expression of CD151 and/or integrin α3ß1 was evaluated in ILC samples (N=117) using immunohistochemistry. The findings were analysed in relation to our results from an IDC cohort (N=182) demonstrating a prognostic value of an expression of CD151/integrin α3ß1 complex in patients with HER2-negative tumours. RESULTS: Unlike in the IDCs, neither CD151 nor CD151/α3ß1 complex showed any correlation with any of the ILC characteristics. Lack of both CD151 and α3ß1 was significantly correlated with poor survival (P=0.034) in lymph node-negative ILC N(-) cases. The CD151(-)/α3ß1(-) patients had 3.12-fold higher risk of death from BCa in comparison with the rest of the ILC N(-) patients. CONCLUSIONS: Biological role of CD151/α3ß1 varies between ILC and IDC. Assessment of CD151/α3ß1 might help to identify ILC N(-) patients with increased risk of distant metastases.
Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Integrina alfa3beta1/metabolismo , Linfonodos/patologia , Tetraspanina 24/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismoRESUMO
Progesterone receptor (PR) and its specific ligand play a key role in development and physiology of mammary gland. The role of PR in initiation and progression of breast carcinoma (BCa) is unquestionable, although molecular mechanism of PR action is complex and not fully understood. It is known that increased risk of breast cancer is associated with progestin-based (synthetic ligands of progesterone) hormonal contraception or hormone replacement therapies. It is estimated that ER/PR-positive tumours represent approximately 50-70% of all BCa cases, and the loss of PR is associated with resistance to hormonal therapy and increased tumour invasiveness. In classical, genomic signalling pathway cytoplasmic PR, following ligand binding, translocates to the nucleus and regulates expression of genes with the PRE sequence. PR is also involved in a large number of alternative, non-genomic signalling cascades, e.g. PR is able to activate MAPK and PI3K/AKT pathways, which leads to regulation of gene expression. The cross-talk between PR and Growth Factors Receptors (GFR) results in progesterone-independent activation of PR as well as PR-regulated GFR expression and activation. Growth factors signalling promotes formation of a pool of hypersensitive PR responsive to even very low ligand concentration. Transcriptional activity of PR as well as its dynamic impact on processes such as cell migration and adhesion are crucial for BCa progression. Further studies of multifaceted mechanisms of PR action may contribute to new PR-targeting therapeutic strategies for breast cancer patients.
Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Receptores de Progesterona/metabolismo , Transdução de Sinais , Neoplasias da Mama/etiologia , Neoplasias da Mama/patologia , Carcinogênese , Feminino , Humanos , Invasividade Neoplásica , Receptores de Progesterona/genéticaRESUMO
Originally identified as a molecular organizer of interacting proteins into tetraspanin-enriched microdomains, the tetraspanin CD151 has now been shown to be involved in tumour progression. Increasing evidence emerging from in vitro, in vivo and clinical analyses implicates this tetraspanin in supporting growth of various types of tumours at different levels. It affects both cell autonomous behavior and communication with neighboring cells and the microenvironment. CD151 regulates post-adhesion events, that is, cell spreading, migration and invasion including subsequent intravasation and formation of metastasis. Present on both neoplastic and endothelial cells, CD151 is engaged in promotion of tumour neovascularization. The molecular mechanism of CD151 in cancer is based on its ability to organize distribution and function of interacting proteins, ie, laminin-binding integrins (α3ß1, α6ß1 and α6ß4), receptors for growth factors (HGFR, EGFR and TGF-ß1R) and matrix metalloproteinases (MMP-7, MMP-2 and MMP-9), which indicates its importance in disease development. Results of clinical analyses of CD151 expression in different types of cancer and a large number of in vivo models demonstrate its impact on tumour growth and invasion and implicate CD151 as a valuable diagnostic and prognostic marker as well as a potential target for anti-cancer therapy.
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Neoplasias/imunologia , Neoplasias/patologia , Tetraspanina 24/imunologia , Animais , Progressão da Doença , Humanos , Metástase Neoplásica , Microambiente TumoralRESUMO
Transmembrane proteins of the tetraspanin superfamily are implicated in a broad spectrum of cellular processes in many biological systems in both health and disease. Tetraspanins form specialized membrane microdomains on the cell surface which control cell proliferation and migration through various adhesion and growth factor receptors. Recent extensive research has shown that expression of various tetraspanins and their associated partners is deregulated in human malignancies. Although, for the most part, the degree of involvement of tetraspanins in carcinogenesis remains to be established, increasing evidence suggests that these proteins might be of clinical significance in at least some malignancies. Here we provide a comprehensive review of the existing data on expression of tetraspanins in breast cancer and other human epithelial tumours, with an emphasis on their value as potential prognostic markers.
Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Epiteliais e Glandulares/metabolismo , Antígenos CD/metabolismo , Neoplasias da Mama/metabolismo , Feminino , Humanos , Proteína Kangai-1/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/metabolismo , Tetraspanina 24 , Tetraspanina 29RESUMO
Increasing evidence suggests that the significance of the tumour immune microenvironment (TIME) for disease prognostication in invasive breast carcinoma is subtype-specific but equivalent studies in ductal carcinoma in situ (DCIS) are limited. The purpose of this paper is to review the existing data on immune cell composition in DCIS in relation to the clinicopathological features and molecular subtype of the lesion. We discuss the value of infiltration by various types of immune cells and the PD-1/PD-L1 axis as potential markers of the risk of recurrence. Analysis of the literature available in PubMed and Medline databases overwhelmingly supports an association between densities of infiltrating immune cells, traits of immune exhaustion, the foci of microinvasion, and overexpression of HER2. Moreover, in several studies, the density of immune infiltration was found to be predictive of local recurrence as either in situ or invasive cancer in HER2-positive or ER-negative DCIS. In light of the recently reported first randomized DCIS trial, relating recurrence risk with overexpression of HER2, we also include a closing paragraph compiling the latest mechanistic data on a functional link between HER2 and the density/composition of TIME in relation to its potential value in the prognostication of the risk of recurrence.
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We have recently demonstrated that fibroblast growth factor receptor 2 (FGFR2)-mediated signalling alters progesterone receptor (PR) activity and response of oestrogen receptor α (ER)-positive (ER+) breast cancer (BCa) cell lines to anti-ER agents. Little is known about whether the crosstalk between ER and PR, shown to be modulated by the hormonal background, might also be affected by FGFR2. Here, PR-dependent behaviour of ER+ BCa cells was studied in the presence of oestrogen (E2) and progesterone (P4) and/or FGF7. In vitro analyses showed that FGF7/FGFR2 signalling: (a) abolished the effect of P4 on E2-promoted 3D cell growth and response to tamoxifen; (b) regulated ER and PR expression and activity; (c) increased formation of ER-PR complexes; and (d) reversed P4-triggered deregulation of ER-dependent genes. Analysis of clinical data demonstrated that the prognostic value of FGFR2 varied between patients with different menopausal status; that is, high expression of FGFR2 was significantly associated with longer progression-free survival (PFS) in postmenopausal patients, whereas there was no significant association in premenopausal patients. FGFR2 was found to positively correlate with the expression of JunB proto-oncogene, AP-1 transcription factor subunit (JUNB), an ER-dependent gene, only in premenopausal patients. Molecular analyses revealed that the presence of JunB was a prerequisite for FGFR2-mediated abrogation of P4-induced inhibition of cell growth. Our results demonstrate for the first time that the FGF7/FGFR2-JunB axis abolishes the modulatory effects of PR on ER-associated biological functions in premenopausal ER+ BCa. This may provide foundations for a better selection of patients for FGFR-targeting therapeutic strategies.
Assuntos
Neoplasias da Mama , Fator 7 de Crescimento de Fibroblastos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Fatores de Transcrição , Neoplasias da Mama/genética , Feminino , Fator 7 de Crescimento de Fibroblastos/genética , Fator 7 de Crescimento de Fibroblastos/metabolismo , Humanos , Progesterona/farmacologia , Progesterona/uso terapêutico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores de Progesterona/metabolismo , Transdução de Sinais , Tamoxifeno/uso terapêutico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
We present here an assessment of a 'real-life' value of automated machine learning algorithm (AI) for examination of immunohistochemistry for fibroblast growth factor receptor-2 (FGFR2) in breast cancer (BC). Expression of FGFR2 in BC (n = 315) measured using a certified 3DHistech CaseViewer/QuantCenter software 2.3.0. was compared to the manual pathologic assessment in digital slides (PA). Results revealed: (i) substantial interrater agreement between AI and PA for dichotomized evaluation (Cohen's kappa = 0.61); (ii) strong correlation between AI and PA H-scores (Spearman r = 0.85, p < 0.001); (iii) a small constant error and a significant proportional error (Passing-Bablok regression y = 0.51 × X + 29.9, p < 0.001); (iv) discrepancies in H-score in cases of extreme (strongest/weakest) or heterogeneous FGFR2 expression and poor tissue quality. The time of AI was significantly longer (568 h) than that of the pathologist (32 h). This study shows that the described commercial machine learning algorithm can reliably execute a routine pathologic assessment, however, in some instances, human expertise is essential.
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There are data to suggest that some ductal carcinoma in situ (DCIS) may evolve through an evolutionary bottleneck, where minor clones susceptible to the imposed selective pressure drive disease progression. Here, we tested the hypothesis that an impact of the inflammatory environment on DCIS evolution is HER2-dependent, conferring proliferative dominance of HER2-negative cells. In tissue samples, density of tumour-infiltrating immune cells (TIICs) was associated only with high tumour nuclear grade, but in 9% of predominantly HER2-negative cases, the presence of tumoral foci ('hot-spots') of basal-like cells with HIF1-α activity adjacent to the areas of dense stromal infiltration was noted. Results of in vitro analyses further demonstrated that IL-1ß and TNF-α as well as macrophage-conditioned medium triggered phosphorylation of NF-κB and subsequent upregulation of COX2 and HIF1-α, exclusively in HER2-negative cells. Treatment with both IL-1ß and TNF-α resulted in growth stimulation and inhibition of HER2-negative and HER2-positive cells, respectively. Moreover, ectopic overexpression of HIF1-α rescued HER2-positive cells from the negative effect of IL-1ß and TNF-α on cell growth. Our data provide novel insight into the molecular basis of HER2-dependent proliferation of DCIS cells and indicate the NF-κB/COX2â¯ââ¯HIF1-α signalling axis as a dominant mechanism of DCIS evolution induced by inflammatory microenvironment. Presented findings also highlight the clinical significance of heterogeneity of DCIS tumours and suggest that HIF1-α might be considered as a predictive marker of disease progression.
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Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Carcinoma Intraductal não Infiltrante/etiologia , Carcinoma Intraductal não Infiltrante/metabolismo , Ciclo-Oxigenase 2/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , NF-kappa B/metabolismo , Biomarcadores , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Linhagem Celular Tumoral , Citocinas/metabolismo , Células Epiteliais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imuno-Histoquímica , Mediadores da Inflamação , Gradação de Tumores , Estadiamento de Neoplasias , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transdução de Sinais , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologiaRESUMO
Interaction between fibroblast growth factor receptor 2 (FGFR2) and estrogen/progesterone receptors (ER/PR) affects resistance to anti-ER therapies, however the prognostic value of FGFR2 in breast cancer (BCa) remains largely unexplored. We have recently showed in vitro that FGFR2-mediated signaling alters PR activity and response to anti-ER treatment. Herein, prognostic significance of FGFR2 in BCa was evaluated in relation to both ER/PR protein status and a molecular signature designed to reflect PR transcriptional activity. FGFR2 was examined in 353 BCa cases using immunohistochemistry and Nanostring-based RNA quantification. FGFR2 expression was higher in ER+PR+ and ER+PR- compared to ER-PR- cases (p < 0.001). Low FGFR2 was associated with higher grade (p < 0.001), higher Ki67 proliferation index (p < 0.001), and worse overall and disease-free survival (HR = 2.34 (95% CI: 1.26-4.34), p = 0.007 and HR = 2.22 (95% CI: 1.25-3.93), p = 0.006, respectively). The poor prognostic value of low FGFR2 was apparent in ER+PR+, but not in ER+PR- patients, and it did not depend on the expression level of PR-dependent genes. Despite the functional link between FGFR2 and ER/PR revealed by preclinical studies, the data showed a link between FGFR2 expression and poor prognosis in BCa patients.
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To investigate the potential functional cooperation between p27Kip1 and p130 in vivo, we generated mice deficient for both p27Kip1 and p130. In p27Kip1-/-; p130-/- mice, the cellularity of the spleens but not the thymi is significantly increased compared with that of their p27Kip1-/- counterparts, affecting the lymphoid, erythroid, and myeloid compartments. In vivo cell proliferation is significantly augmented in the B and T cells, monocytes, macrophages, and erythroid progenitors in the spleens of p27Kip1-/-; p130-/- animals. Immunoprecipitation and immunodepletion studies indicate that p130 can compensate for the absence of p27Kip1 in binding to and repressing CDK2 and is the predominant CDK-inhibitor associated with the inactive CDK2 in the p27Kip1-/- splenocytes. The finding that the p27Kip1-/-; p130-/- splenic B cells are hypersensitive to mitogenic stimulations in vitro lends support to the concept that the hyperproliferation of splenocytes is not a result of the influence of their microenvironment. In summary, our findings provide genetic and molecular evidence to show that p130 is a bona fide cyclin-dependent kinase inhibitor and cooperates with p27Kip1 to regulate hematopoietic cell proliferation in vivo.
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Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Sistema Hematopoético/citologia , Proteína p130 Retinoblastoma-Like/metabolismo , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Antígenos de Grupos Sanguíneos/imunologia , Complexo CD3/imunologia , Ciclo Celular , Células Cultivadas , Quinase 2 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/deficiência , Antígenos Comuns de Leucócito/imunologia , Camundongos , Camundongos Knockout , Ligação Proteica , Proteína p130 Retinoblastoma-Like/deficiência , Baço/citologia , Timo/citologia , Timo/imunologia , Regulação para Cima/genéticaRESUMO
As dissemination through blood and lymph is the critical step of the metastatic cascade, circulating tumour cells (CTCs) have attracted wide attention as a potential surrogate marker to monitor progression into metastatic disease and response to therapy. In patients with invasive breast carcinoma (IBC), CTCs are being considered nowadays as a valid counterpart for the assessment of known prognostic and predictive factors. Molecular characterization of CTCs using protein detection, genomic and transcriptomic panels allows to depict IBC biology. Such molecular profiling of circulating cells with increased metastatic abilities appears to be essential, especially after tumour resection, as well as in advanced disseminated disease, when information crucial for identification of therapeutic targets becomes unobtainable from the primary site. If CTCs are truly representative of primary tumours and metastases, characterization of the molecular profile of this easily accessible 'biopsy' might be of prime importance for clinical practice in IBC patients. This review summarizes available data on feasibility and documented benefits of monitoring of essential IBC biological features in CTCs, with special reference to multifactorial proteomic, genomic, and transcriptomic panels of known prognostic or predictive value.
RESUMO
Stromal stimuli mediated by growth factor receptors, leading to ligand-independent activation of steroid hormone receptors, have long been implicated in development of breast cancer resistance to endocrine therapy. Mutations in fibroblast growth factor receptor (FGFR) genes have been associated with a higher incidence and progression of breast cancer. Increasing evidence suggests that FGFR-mediated interaction between luminal invasive ductal breast carcinoma (IDC) and its microenvironment contributes to the progression to hormone-independence. Therapeutic strategies based on FGFR inhibitors hold promise for overcoming resistance to the ER-targeting treatment. A series of excellent reviews discuss a potential role of FGFR in development of IDC. Here, we provide a concise updated summary of existing literature on FGFR-mediated signalling with an emphasis on an interaction between FGFR and estrogen/progesterone receptors (ER/PR) in IDC. Focusing on the regulatory role of tumour microenvironment in the activity of steroid hormone receptors, we compile the available functional data on FGFRs-mediated signalling, as a fundamental mechanism of luminal IDC progression and failure of anti-ER treatment. We also highlight the translational value of the presented findings and summarize ongoing oncologic clinical trials investigating FGFRs inhibition in interventional studies in breast cancer.