RESUMO
The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain-containing ion transport regulator 3 (FXYD3), a component of the Na+/K+ pump. Accordingly, FXYD3+ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3+ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3+ CSCs were sensitive to senolytic Na+/K+ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3+ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na+/K+ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis.
Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Células-Tronco Neoplásicas/patologia , Linhagem Celular Tumoral , Proteínas de Membrana , Proteínas de Neoplasias/genéticaRESUMO
PURPOSE: This study aimed to clarify the characteristics of post-traumatic growth (PTG) among adolescents having mothers diagnosed with breast cancer and the relationship between PTG and cancer-related communication with breast cancer survivors. METHODS: A cross-sectional study was conducted using anonymous self-report questionnaires with breast cancer survivors and adolescent children. PTG in adolescents was measured using the Japanese version of the revised PTG Inventory for Children (PTGI-C-R-J). Furthermore, hierarchical multiple regression analysis was implemented. To evaluate the impact of cancer-related communication on each subscale, the total score of cancer-related communication was switched with other subscales individually within the constructed model. RESULTS: A total of 97 breast cancer survivors and their adolescent children were included. The mean scores of the total PTGI-C-R-J and subscale scores for "personal strength," "new possibilities," "relating to others," "appreciation of life," and "spiritual change" were 9.0, 1.7, 1.8, 2.3, 2.4, and 0.9, respectively. The connection between PTG and cancer-related communication was partially clarified. The PTGI-C-R-J score was higher when adolescents shared more information regarding breast cancer with their mothers and lower when adolescents expressed more negative feelings toward their mothers. Communication regarding relationships with mothers was not correlated with PTG. CONCLUSIONS: Of all PTG domains, "relating to others" and "appreciation of life" were comparatively higher in adolescents. Health professionals should support breast cancer survivors to ensure that they convey appropriate information regarding their treatment plans and side effects to their adolescent children. Health professionals should help adolescent children express their negative feelings calmly and clearly.
Assuntos
Neoplasias da Mama , Crescimento Psicológico Pós-Traumático , Transtornos de Estresse Pós-Traumáticos , Criança , Humanos , Adolescente , Feminino , Estudos Transversais , Sobreviventes , Comunicação , Adaptação PsicológicaRESUMO
Information regarding patients who were treated for breast cancer in 2018 was extracted from the National Clinical Database (NCD), which is run by Japanese physicians. This database continues from 1975, created by the Japanese Breast Cancer Society (JBCS). A total of 95,620 breast cancer cases were registered. The demographics, clinical characteristics, pathology, surgical treatment, adjuvant chemotherapy, adjuvant endocrine therapy, and radiation therapy of Japanese breast cancer patients were summarized. We made comparisons with other reports to reveal the characteristics of our database. We also described some features in Japanese breast cancer that changed over time. The unique characteristics of breast cancer patients in Japan may provide guidance for future research and improvement in healthcare services.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/terapia , Neoplasias da Mama/tratamento farmacológico , Japão/epidemiologia , Terapia Combinada , Quimioterapia Adjuvante , Bases de Dados FactuaisRESUMO
AIM: Postmastectomy radiotherapy (PMRT) is the standard treatment for locally advanced breast cancer. However, the effectiveness of PMRT in patients with pT1-2 and N1 tumours remains controversial. Therefore, this study aimed to determine the prognostic impact of PMRT in patients with breast cancer and with pT1-2 and 1-3 lymph node metastases. METHODS: Using data from the Japanese National Clinical Database from 2004 to 2012, we evaluated the association of PMRT with locoregional recurrence (LRR), any recurrence, and mortality. We enrolled patients who had undergone mastectomy and axillary node dissection and were diagnosed with pT1-2 and N1. We compared clinicopathological factors and prognosis between patients who received (PMRT group) and those who did not receive (No-PMRT group) PMRT. RESULTS: Among 8914 patients enrolled, 492 patients belonged to the PMRT group and 8422 to the No-PMRT group. The median observation time was 6.3 years. There was no significant difference in the incidences of LRR (4.0% versus 5.0%, P = 0.61), recurrence (13.8% versus 11.8%, P = 0.23) and breast cancer death (6.0% versus 4.3%, P = 0.08) at 5 years between the groups. Multivariable analysis revealed that LRR was significantly associated with tumour size, number of node metastases and triple-negative subtype but not with PMRT. CONCLUSIONS: The LRR rate in the No-PMRT group was 5.0% at 5 years among patients with T1-2 and N1. PMRT did not significantly influence LRR in patients with T1-2 and N1. However, PMRT administration should be tailored considering the individual risks of tumour size, 3 node metastases and triple-negative subtype.
Assuntos
Neoplasias da Mama , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Japão/epidemiologia , Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática/patologia , Mastectomia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Radioterapia Adjuvante , Sistema de Registros , Estudos RetrospectivosRESUMO
BACKGROUND: Eribulin therapy has been reported to prolong overall survival (OS) but not progression-free survival, probably because it prevents the development of metastatic lesions; however, this effect has not yet been confirmed. METHODS: We reviewed the medical charts of 50 patients with metastatic breast cancer who underwent eribulin monotherapy at our hospital between 2014 and 2019. Patients were divided into two groups, namely, those who discontinued eribulin because of disease progression due to development of new lesions (NL group) and those who discontinued eribulin for other reasons, such as lesion growth and unacceptable side effects (non-NL group). Survival times were estimated for both groups and we investigated if eribulin-mediated suppression of new metastasis increased OS. RESULTS: Median OS for all patients, from eribulin initiation, was 14.4 months (range 1.2-60.1), whereas it was 4.6 months (range 1.7-24.7) in the NL group and 16.8 months (range 1.2-60.1) in the non-NL group. OS was significantly poorer in the NL group than in the non-NL group (p < 0.05). CONCLUSION: Eribulin monotherapy-mediated suppression of new metastatic lesions results in a better prognosis in patients with metastatic breast cancer.
Assuntos
Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Resultado do Tratamento , Furanos/uso terapêutico , Cetonas/uso terapêutico , Prognóstico , Metástase Neoplásica , Antineoplásicos/uso terapêuticoRESUMO
BACKGROUND: Breast augmentation has been linked to various complications, including cancerous tumors. The majority type of breast cancer associated with breast augmentation is adenocarcinoma. Primary squamous cell carcinoma (SCC) of the breast is extremely rare in both augmented and non-augmented women. Due to the low incidence, the possible origin and the mechanism of carcinogenesis of the breast SCC are not well understood. Here, we report a rare case of pure SCC 16 years after breast augmentation with liquid silicone injection. CASE PRESENTATION: A 51-year-old Japanese woman was suffered from prolonged breast fluid retention in her left breast. Multiple unknown foreign bodies caused difficulties to investigate the inflammatory focus with ultrasonography. After unsuccessful surgical drainage and antibiotics treatments, the long-standing fluid retention was surgically removed and pathologically investigated. SCC was found in the removed tissue, and the patient underwent a total left mastectomy followed by postoperative chemotherapy. Pathological analysis revealed multiple cystic structures with a hard shell which enclosed high viscous liquid. A qualitative analysis using a Fourier transform infrared spectroscope defined the liquid as pure silicon, which possibly caused the squamous cell carcinogenesis. CONCLUSIONS: Although liquid silicone injection is not a current option for breast augmentation, the injected silicone could result in cancerous tumor generation after years. This case revealed that unphysiological substances could lead to unexpected biological reactions, which caused difficulties in diagnosis with our routine examination. It will be required that accumulate information from more cases and develop novel diagnostic equipment and biomarkers to address these artificial substance-derived tumors.
RESUMO
AIM: Anxiety and its correlates in parents of patients with breast cancer have rarely been studied. We explored anxiety among parents of postoperative patients with breast cancer and its relationship with parents' social support and care needs and patients' anxiety. METHODS: A cross-sectional survey using self-report questionnaires and medical records was conducted among patients with breast cancer after surgery and their parents at four designated cancer care hospitals between September 2015 and June 2016. Anxiety was measured using the Hospital Anxiety and Depression Scale (HADS). Parents provided information about social support and care needs. Multilevel analysis was performed on patient-parent paired data controlling for patient-level variation. RESULTS: Participants included 107 patients, 83 mothers, and 51 fathers. The mean HADS anxiety scores reported by mothers and fathers were 7.2 and 6.5, respectively, which were higher than patients' HADS anxiety scores. Fulfillment of important care needs was related to lower anxiety among mothers and fathers (estimate = -1.38, p = .01). Lower family support and higher patient anxiety were associated with higher anxiety in mothers, but not fathers. CONCLUSIONS: Parents of patients with breast cancer had high anxiety. Communication, providing cancer-related information, and fulfilling care needs can alleviate anxiety in parents of patients with breast cancer after surgery. Furthermore, increasing family support and decreasing patients' anxiety are essential to alleviating mothers' anxiety.
Assuntos
Neoplasias da Mama , Ansiedade , Neoplasias da Mama/cirurgia , Estudos Transversais , Depressão , Pai , Feminino , Humanos , Japão , Masculino , Mães , Pais , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Surgical treatment of breast cancer patients aged 85 years or older is still controversial. METHODS: A series of surgically treated breast cancer patients aged 85 years or older was evaluated. The clinicopathological features and outcomes of these patients were compared with the features and outcomes of breast cancer patients in the same age group who were managed without surgery. RESULTS: A total of 45 patients (75%) received surgical treatment, and 15 patients (25%) were managed without surgery. Significantly more patients treated by surgery underwent systemic treatment than patients managed without surgery (P = .003). The 5-year disease-free survival rate of patients treated by surgery was 80.7% (95% confidence interval: 66.2-98.5%), which was significantly higher than that of the patients managed without surgery (P = .001). CONCLUSIONS: The surgical treatment of breast cancer patients aged 85 years or older is warranted. This outcome was achieved with the use of hormonal therapy.
Assuntos
Neoplasias da Mama/cirurgia , Fatores Etários , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Feminino , Humanos , Mastectomia/métodos , Mastectomia/mortalidade , Radioterapia , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Cancer stem-like cells (CSCs) induce drug resistance and recurrence of tumors when they experience DNA replication stress. However, the mechanisms underlying DNA replication stress in CSCs and its compensation remain unclear. Here, we demonstrate that upregulated c-Myc expression induces stronger DNA replication stress in patient-derived breast CSCs than in differentiated cancer cells. Our results suggest critical roles for mini-chromosome maintenance protein 10 (MCM10), a firing (activating) factor of DNA replication origins, to compensate for DNA replication stress in CSCs. MCM10 expression is upregulated in CSCs and is maintained by c-Myc. c-Myc-dependent collisions between RNA transcription and DNA replication machinery may occur in nuclei, thereby causing DNA replication stress. MCM10 may activate dormant replication origins close to these collisions to ensure the progression of replication. Moreover, patient-derived breast CSCs were found to be dependent on MCM10 for their maintenance, even after enrichment for CSCs that were resistant to paclitaxel, the standard chemotherapeutic agent. Further, MCM10 depletion decreased the growth of cancer cells, but not of normal cells. Therefore, MCM10 may robustly compensate for DNA replication stress and facilitate genome duplication in cancer cells in the S-phase, which is more pronounced in CSCs. Overall, we provide a preclinical rationale to target the c-Myc-MCM10 axis for preventing drug resistance and recurrence of tumors.
Assuntos
Neoplasias da Mama/genética , Proteínas de Manutenção de Minicromossomo/metabolismo , Recidiva Local de Neoplasia/genética , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Dano ao DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Proteínas de Manutenção de Minicromossomo/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Células-Tronco Neoplásicas/efeitos dos fármacos , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Esferoides Celulares , Células Tumorais Cultivadas , Regulação para CimaRESUMO
Cancer stem-like cells (CSCs) are expanded in the CSC niche by increased frequency of symmetric cell divisions at the expense of asymmetric cell divisions. The symmetric division of CSCs is important for the malignant properties of cancer; however, underlying molecular mechanisms remain largely elusive. Here, we show a cytokine, semaphorin 3 (Sema3), produced from the CSC niche, induces symmetric divisions of CSCs to expand the CSC population. Our findings indicate that stimulation with Sema3 induced sphere formation in breast cancer cells through neuropilin 1 (NP1) receptor that was specifically expressed in breast CSCs (BCSCs). Knockdown of MICAL3, a cytoplasmic Sema3 signal transducer, greatly decreased tumor sphere formation and tumor-initiating activity. Mechanistically, Sema3 induced interaction among MICAL3, collapsin response mediator protein 2 (CRMP2), and Numb. It appears that activity of MICAL3 monooxygenase (MO) stimulated by Sema3 is required for tumor sphere formation, interaction between CRMP2 and Numb, and accumulation of Numb protein. We found that knockdown of CRMP2 or Numb significantly decreased tumor sphere formation. Moreover, MICAL3 knockdown significantly decreased Sema3-induced symmetric divisions in NP1/Numb-positive BCSCs and increased asymmetric division that produces NP1/Numb negative cells without stem-like properties. In addition, breast cancer patients with NP1-positive cancer tissues show poor prognosis. Therefore, the niche factor Sema3-stimulated NP1/MICAL3/CRMP2/Numb axis appears to expand CSCs at least partly through increased frequency of MICAL3-mediated symmetric division of CSCs.
Assuntos
Neoplasias da Mama/metabolismo , Divisão Celular , Oxigenases de Função Mista/metabolismo , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Semaforina-3A/metabolismo , Transdução de Sinais , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Oxigenases de Função Mista/genética , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/patologia , Semaforina-3A/genética , Esferoides Celulares/metabolismo , Esferoides Celulares/patologiaRESUMO
Cyclin-dependent kinase (CDK) 4 and CDK6 inhibitors are effective therapeutic options for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Although CDK4/6 inhibitors mainly target the cyclin D-CDK4/6-retinoblastoma tumor suppressor protein (RB) axis, little is known about the clinical impact of inhibiting phosphorylation of other CDK4/6 target proteins. Here, we focused on other CDK4/6 targets, SMAD proteins. We showed that a CDK4/6 inhibitor palbociclib and activin-SMAD2 signaling cooperatively inhibited cell cycle progression of a luminal-type breast cancer cell line T47D. Palbociclib enhanced SMAD2 binding to the genome by inhibiting CDK4/6-mediated linker phosphorylation of the SMAD2 protein. We also showed that cyclin G2 plays essential roles in SMAD2-dependent cytostatic response. Moreover, comparison of the SMAD2 ChIP-seq data of T47D cells with those of Hs578T (triple-negative breast cancer cells) indicated that palbociclib augmented different SMAD2-mediated functions based on cell type, and enhanced SMAD2 binding to the target regions on the genome without affecting its binding pattern. In summary, palbociclib enhances the cytostatic effects of the activin-SMAD2 signaling pathway, whereas it possibly strengthens the tumor-promoting aspect in aggressive breast cancer.
Assuntos
Ativinas/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Receptores de Estrogênio/metabolismo , Proteína Smad2/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Citostáticos/farmacologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteína Smad2/genéticaRESUMO
Breast cancer remains a common malignancy in women, but the take-up for breast cancer screening programs in Japan is still low, possibly due to its perceived inconvenience. TFF1 and TFF3 are expressed in both breast cancer tissue and normal breast. Serum trefoil proteins were reported as cancer screening markers for gastric, prostate, lung, pancreatic cancer and cholangio carcinoma. The purpose of this study was to examine whether serum trefoil proteins could be screening biomarkers for breast cancer. Serum trefoil proteins in 94 breast cancer patients and 84 health check females were measured by ELISA. Serum TFF1 and TFF3 were significantly higher and serum TFF2 was significantly lower in breast cancer patients. Area under the curve of receiver operating characteristic of TFF1, TFF2, and TFF3 was 0.69, 0.83, and. 0.72, respectively. AUC of the combination of TFF1, TFF2, and TFF3 was 0.96. Immunohistochemically, TFF1 expression was positive in 56.5% and TFF3 was positive in 73.9% of breast cancers, while TFF2 was negative in all tumors. Serum TFF1 had positive correlation with expression of TFF1 in breast cancer tissue. Serum concentrations of TFF1 and TFF3 but not TFF2 are higher in women with breast cancer than in women without breast cancer.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/patologia , Soro/química , Fator Trefoil-1/sangue , Fator Trefoil-2/sangue , Fator Trefoil-3/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , JapãoRESUMO
Triple-negative breast cancer (TNBC) cells do not express estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2. Currently, apart from poly ADP-ribose polymerase inhibitors, there are few effective therapeutic options for this type of cancer. Here, we present comprehensive characterization of the genetic alterations in TNBC performed by high coverage whole genome sequencing together with transcriptome and whole exome sequencing. Silencing of the BRCA1 gene impaired the homologous recombination pathway in a subset of TNBCs, which exhibited similar phenotypes to tumors with BRCA1 mutations; they harbored many structural variations (SVs) with relative enrichment for tandem duplication. Clonal analysis suggested that TP53 mutations and methylation of CpG dinucleotides in the BRCA1 promoter were early events of carcinogenesis. SVs were associated with driver oncogenic events such as amplification of MYC, NOTCH2, or NOTCH3 and affected tumor suppressor genes including RB1, PTEN, and KMT2C. Furthermore, we identified putative TGFA enhancer regions. Recurrent SVs that affected the TGFA enhancer region led to enhanced expression of the TGFA oncogene that encodes one of the high affinity ligands for epidermal growth factor receptor. We also identified a variety of oncogenes that could transform 3T3 mouse fibroblasts, suggesting that individual TNBC tumors may undergo a unique driver event that can be targetable. Thus, we revealed several features of TNBC with clinically important implications.
Assuntos
Proteína BRCA1/genética , Transcriptoma/genética , Neoplasias de Mama Triplo Negativas/genética , Proteína Supressora de Tumor p53/genética , Células 3T3 , Animais , Metilação de DNA/genética , Exoma/genética , Feminino , Amplificação de Genes , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Recombinação Homóloga/genética , Humanos , Camundongos , Mutação , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
In 2014, the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) reported that post-mastectomy radiation therapy (PMRT) for breast cancer patients with 1-3 cancer-positive lymph nodes is associated with a survival benefit. However, it is not known whether this applies to Japanese patients in daily clinical practice, because this conclusion was based on the results of older, western trials. Therefore, we studied the differences between PMRT results in western breast cancer patients and current practice in Japanese patients. Although we identified three differences, they do not appear to strongly impact the results of EBCTCG. We conclude that Japanese breast cancer patients with 1-3 positive lymph nodes should receive PMRT in daily clinical practice.
Assuntos
Neoplasias da Mama/radioterapia , Linfonodos/patologia , Mastectomia , Recidiva Local de Neoplasia/radioterapia , Radioterapia Adjuvante , Biópsia de Linfonodo Sentinela , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Terapia Combinada , Feminino , Humanos , Metanálise como Assunto , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Cuidados Pós-Operatórios , PrognósticoRESUMO
Epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition MET, are crucial in several stages of cancer metastasis. Epithelial-mesenchymal transition allows cancer cells to move to proximal blood vessels for intravasation. However, because EMT and MET processes are dynamic, mesenchymal cancer cells are likely to undergo MET transiently and subsequently re-undergo EMT to restart the metastatic process. Therefore, spatiotemporally coordinated mutual regulation between EMT and MET could occur during metastasis. To elucidate such regulation, we chose HCC38, a human triple-negative breast cancer cell line, because HCC38 is composed of epithelial and mesenchymal populations at a fixed ratio even though mesenchymal cells proliferate significantly more slowly than epithelial cells. We purified epithelial and mesenchymal cells from Venus-labeled and unlabeled HCC38 cells and mixed them at various ratios to follow EMT and MET. Using this system, we found that the efficiency of EMT is approximately an order of magnitude higher than that of MET and that the two populations significantly enhance the transition of cells from the other population to their own. In addition, knockdown of Zinc finger E-box-binding homeobox 1 (ZEB1) or Zinc finger protein SNAI2 (SLUG) significantly suppressed EMT but promoted partial MET, indicating that ZEB1 and SLUG are crucial to EMT and MET. We also show that primary breast cancer cells underwent EMT that correlated with changes in expression profiles of genes determining EMT status and breast cancer subtype. These changes were very similar to those observed in EMT in HCC38 cells. Consequently, we propose HCC38 as a suitable model to analyze EMT-MET dynamics that could affect the development of triple-negative breast cancer.
Assuntos
Transição Epitelial-Mesenquimal/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células-Tronco Mesenquimais/patologia , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genéticaRESUMO
Cancer stem cells are thought to be responsible for tumor growth, recurrence, and resistance to conventional cancer therapy. However, it is still unclear how they are maintained in tumor tissues. Here, we show that the growth differentiation factor 15 (GDF15), a member of the TGFß family, may maintain cancer stem-like cells in breast cancer tissues by inducing its own expression in an autocrine/paracrine manner. We found that GDF15, but not TGFß, increased tumor sphere formation in several breast cancer cell lines and patient-derived primary breast cancer cells. As expected, TGFß strongly stimulated the phosphorylation of Smad2. GDF15 also stimulated the phosphorylation of Smad2, but the GDF15-induced tumor sphere forming efficiency was not significantly affected by treatment with SB431542, an inhibitor of the TGFß signaling. Although TGFß transiently activated ERK1/2, GDF15 induced prolonged activation of ERK1/2. Treatment with U0126, an inhibitor of the MEK-ERK1/2 signaling, greatly inhibited the GDF15-induced tumor sphere formation. Moreover, cytokine array experiments revealed that GDF15, but not TGFß, is able to induce its own expression; furthermore, it appears to form an autocrine/paracrine circuit to continuously produce GDF15. In addition, we found heterogeneous expression levels of GDF15 among cancer cells and in human breast cancer tissues using immunohistochemistry. This may reflect a heterogeneous cancer cell population, including cancer stem-like cells and other cancer cells. Our findings suggest that GDF15 induces tumor sphere formation through GDF15-ERK1/2-GDF15 circuits, leading to maintenance of GDF15high cancer stem-like cells. Targeting GDF15 to break these circuits should contribute to the eradication of tumors.
Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Fator 15 de Diferenciação de Crescimento/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Comunicação Autócrina , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Feminino , Humanos , Sistema de Sinalização das MAP Quinases , Células MCF-7 , Comunicação ParácrinaRESUMO
PURPOSE: Digital polymerase chain reaction (dPCR) has been used to yield an absolute measure of nucleic acid concentrations. Recently, a new method referred to as droplet digital PCR (ddPCR) has gained attention as a more precise and less subjective assay to quantify DNA amplification. We demonstrated the usefulness of ddPCR to determine HER2 gene amplification of breast cancer. METHODS: In this study, we used ddPCR to measure the HER2 gene copy number in clinical formalin-fixed paraffin-embedded samples of 41 primary breast cancer patients. To improve the accuracy of ddPCR analysis, we also estimated the tumor content ratio (TCR) for each sample. RESULTS: Our determination method for HER2 gene amplification using the ddPCR ratio (ERBB2:ch17cent copy number ratio) combined with the TCR showed high consistency with the conventionally defined HER2 gene status according to ASCO-CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines (P<0.0001, Fisher's exact test). The equivocal area was established by adopting 99% confidence intervals obtained by cell line assays, which made it possible to identify all conventionally HER2-positive cases with our method. In addition, we succeeded in automating a major part of the process from DNA extraction to determination of HER2 gene status. CONCLUSIONS: The introduction of ddPCR to determine the HER2 gene status in breast cancer is feasible for use in clinical practice and might complement or even replace conventional methods of examination in the future.
Assuntos
Neoplasias da Mama/genética , Genes erbB-2 , Reação em Cadeia da Polimerase , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/cirurgia , Linhagem Celular Tumoral , Feminino , Amplificação de Genes , Dosagem de Genes , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase/métodos , Carga TumoralRESUMO
BACKGROUND: Virtual Touch tissue quantification (VTTQ) is a promising new technology that quantitatively determines the stiffness of tissue. However, the clinical impact of this device on the assessment of breast cancer is unclear. METHODS: This study aimed to review the ultrasound records of patients with breast lesions where VTTQ was used to assess 123 normal breast tissues, 18 benign tumors, and 117 histopathologically confirmed breast cancers in a total of 129 patients. To determine the VTTQ value, a 5×5 mm region of interest was placed in the center of the area of interest, and the target lesion was measured at least three times by VTTQ. RESULTS: Seventy-six percent of the malignant lesions could not be assessed using VTTQ. Among the malignant lesions, ductal carcinomas in situ (DCIS) and invasive breast cancers smaller than 1.6 cm tended to be 'measurable.' Only 17 and 1% of benign breast lesions and areas of normal breast tissue, respectively, were considered to be 'unmeasurable' (P<0.001). CONCLUSIONS: A breast lesion that could not be quantitatively assessed by VTTQ was suspicious for malignancy. By contrast, DCIS lesions and small invasive breast cancers tended to be 'measurable.' These findings indicate that VTTQ may be a useful application for assessing breast tumors.
Assuntos
Neoplasias da Mama/patologia , Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Técnicas de Imagem por Elasticidade/métodos , Ultrassonografia Mamária/instrumentação , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Intraductal não Infiltrante/diagnóstico por imagem , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Palpação , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: The management of cancer in the axillary area depends on the etiology of the tumor. CASE REPORT: A 37-year-old woman presented with a 2 cm mass in the axillary fossa. Core needle biopsy revealed adenocarcinoma. There were no abnormal breast findings on physical examination, mammography, or ultrasonography. However, enhanced magnetic resonance imaging (MRI) and positron emission tomography (PET) showed a segmentally-distributed, abnormal area in the upper-outer quadrant, continuous with the axillary mass. Samples of this area obtained by vacuum-assisted biopsy showed intraductal carcinoma. These findings indicated that the axillary lesion was a part of primary breast cancer originating from the axillary tail. Based on these results, the patient underwent total mastectomy with sentinel lymph node biopsy. Pathological examination of the specimen showed invasive ductal carcinoma accompanied by intraductal carcinoma extending up to 8.5 cm. Our case suggests that enhanced MRI and PET can provide useful preoperative information for the management of axillary breast lesions.