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1.
Clin Imaging ; 96: 38-43, 2023 Apr.
Article in English | MEDLINE | ID: mdl-36773531

ABSTRACT

PURPOSE: To assess the usefulness of amide proton transfer (APT) imaging to predict the biological status of breast cancers. METHOD: Sixty-six patients (age range 31-85 years, mean 58.9 years) with histopathologically proven invasive ductal carcinomas of 2 cm or larger in diameter were included in this study. 3D APT weighted imaging was conducted on a 3 T scanner. Mean APT signal intensity (SI) was analyzed in relation to biological subtypes, Ki-67 labeling index, and nuclear grades (NGs). RESULTS: The triple-negative (TN) cancers (n = 10; 2.75 ± 0.42%) showed significantly higher APT SI than the luminal type cancers (n = 48; 1.74 ± 0.83) and HER2 cancers (n = 8; 1.83 ± 0.21) (P = 0.0007, 0.03). APT SI had weakly positive correlation with the Ki-67 labeling index (r = 0.38, P = 0.002). The mean APT SIs were significantly higher for high-Ki-67 (>30%) (n = 31; 2.25 ± 0.70) than low-Ki-67 (≤30%) cancers (n = 35; 1.60 ± 0.79) (P = 0.0007). There was no significant difference in the APT SIs between NG 1-2 (n = 31; 1.71 ± 0.84) and NG 3 (n = 35; 2.08 ± 0.76%) cancers (P = 0.06). CONCLUSIONS: TN and high-Ki-67 breast cancers showed high APT SIs. APT imaging can help to predict the biological status of breast cancers.


Subject(s)
Brain Neoplasms , Breast Neoplasms , Humans , Adult , Middle Aged , Aged , Aged, 80 and over , Female , Magnetic Resonance Imaging/methods , Protons , Ki-67 Antigen , Amides , Brain Neoplasms/pathology
2.
Mol Cancer Res ; 21(3): 274-289, 2023 03 01.
Article in English | MEDLINE | ID: mdl-36445328

ABSTRACT

The polybromo-1 (PBRM1) chromatin-targeting subunit of the SWI/SNF PBAF chromatin remodeling complex drives DNA damage resistance and immune evasion in certain cancer cells through mechanisms that remain unclear. STAT1 and IRF1 are essential effectors of type I and II IFN pathways. Here, we report that MUC1-C is necessary for PBRM1 expression and that it forms a nuclear complex with PBRM1 in triple-negative breast cancer (TNBC) cells. Analysis of global transcriptional (RNA-seq) and chromatin accessibility (ATAC-seq) profiles further demonstrated that MUC1-C and PBRM1 drive STAT1 and IRF1 expression by increasing chromatin accessibility of promoter-like signatures (PLS) on their respective genes. We also found that MUC1-C, PBRM1, and IRF1 increase the expression and chromatin accessibility on PLSs of the (i) type II IFN pathway IDO1 and WARS genes and (ii) type I IFN pathway RIG-I, MDA5, and ISG15 genes that collectively contribute to DNA damage resistance and immune evasion. In support of these results, targeting MUC1-C in wild-type BRCA TNBC cells enhanced carboplatin-induced DNA damage and the loss of self-renewal capacity. In addition, MUC1-C was necessary for DNA damage resistance, self-renewal, and tumorigenicity in olaparib-resistant BRCA1-mutant TNBC cells. Analysis of TNBC tumors corroborated that (i) MUC1 and PBRM1 are associated with decreased responsiveness to chemotherapy and (ii) MUC1-C expression is associated with the depletion of tumor-infiltrating lymphocytes (TIL). These findings demonstrate that MUC1-C activates PBRM1, and thereby chromatin remodeling of IFN-stimulated genes that promote chronic inflammation, DNA damage resistance, and immune evasion. IMPLICATIONS: MUC1-C is necessary for PBRM1-driven chromatin remodeling in chronic activation of IFN pathway genes that promote DNA damage resistance and immunosuppression.


Subject(s)
Mucin-1 , Transcription Factors , Triple Negative Breast Neoplasms , Humans , Chromatin , DNA Damage , DNA-Binding Proteins/genetics , Immunosuppression Therapy , Interferons/genetics , Mucin-1/genetics , Mucin-1/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology
3.
J Cancer Res Clin Oncol ; 149(8): 4899-4914, 2023 Jul.
Article in English | MEDLINE | ID: mdl-36307557

ABSTRACT

PURPOSE: This study evaluated the reliability, validity, and responsiveness of the Japanese version of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-ELD14 and measured the health-related quality of life (HRQOL) of elderly Japanese patients with cancer aged ≥ 60 and ≥ 70 years. METHODS: The study recruited elderly Japanese patients with cancer aged ≥ 60 (≥ 70) years (n = 1803 [n = 1236]). The EORTC QLQ-ELD14 was evaluated for reliability, validity, responsiveness, and correlations of changes in score between the EORTC QLQ-ELD14 and the EORTC QLQ-C30 before and after the commencement of the COVID-19 pandemic. RESULTS: In both age groups, the proportion of missing items was low (< 3%). Cronbach's α was good at ≥ 0.70, except for two of the seven items. All the intraclass coefficient constants were good at ≥ 0.70. The concurrent validity was good but correlation with the EORTC QLQ-C30 was not strong, except for the hypothesis items. Regarding the assessment of responsiveness, only one item ("maintaining purpose") of the EORTC QLQ-ELD14 worsened (- 6.14 ± 29.20, standard response of mean > 0.2) after the commencement of the COVID-19 pandemic. The changes in score between the EORTC QLQ-ELD14 and the "global health status/QOL" and "summary score" of the EORTC QLQ-C30 had moderate-to-high negative correlations for all items, except two. Hypotheses to evaluate construct validity were accepted at 90%, while responsiveness was accepted at 80%. CONCLUSION: The Japanese version of the EORTC QLQ-ELD14 questionnaire appears to have acceptable reliability, validity, and responsiveness to evaluate HRQOL in elderly Japanese people with cancer.


Subject(s)
Neoplasms , Quality of Life , Aged , Humans , COVID-19/epidemiology , East Asian People , Neoplasms/epidemiology , Neoplasms/therapy , Pandemics , Reproducibility of Results , Surveys and Questionnaires
4.
Cancer Med ; 10(2): 529-539, 2021 01.
Article in English | MEDLINE | ID: mdl-33274848

ABSTRACT

Precision oncology with next generation sequencing (NGS) using tumor tissue with or without blood has begun in Japan. Tumor molecular profiling tests are available, including the OncoGuide™ NCC Oncopanel System and FoundationOne® CDx (F1CDx). Our purpose was to identify potentially actionable genetic alterations in breast cancer with this comprehensive tumor profiling test. We enrolled 115 patients with pathologically diagnosed advanced or metastatic breast cancer. Comprehensive tumor genomic profiling, microsatellite instability, and tumor mutational burden (TMB) were determined using F1CDx. Testing was successful in 109/115 cases (94.8%). Clinically actionable alterations were identified in 76% of advanced breast cancer patients. The most frequent short variants were in TP53 (48.6%), PIK3CA (38.5%), GATA3 (11.0%), PTEN (11.0%), and BRCA1 (10.1%), and structural variants were in ERBB2 (24.8%), MYC (21.1%), RAD21 (21.1%), CCND1 (11.9%), FGF19 (10.1%), and PTEN (10.1%). Regarding human epidermal growth factor receptor (HER)2 status, 106/109 samples (97.2%) were concordant between F1CDx and HER2 testing with immunohistochemistry/fluorescence in situ hybridization. However, ERBB2 amplification was newly detected in four samples and ERBB2 mutations were detected in five HER2-negative breast cancer samples. Oncogenic BRCA mutations were found in three samples with F1CDx among 27 germline testing-negative samples. The mean TMB in all samples was 6.28 mut/Mb and tended to be higher in luminal B and triple-negative breast cancer (mean = 8.1 and 5.9 mut/Mb, respectively) compared with other subtypes. In conclusion, we established a system for precision oncology and obtained preliminary data with NGS as the first step. The information in this clinical sequencing panel will help guide the development of new treatments for breast cancer patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Breast Neoplasms/drug therapy , Gene Expression Profiling , Molecular Targeted Therapy , Mutation , Receptor, ErbB-2/genetics , Adult , Aged , Aged, 80 and over , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Decision Support Techniques , Female , Follow-Up Studies , High-Throughput Nucleotide Sequencing , Humans , Middle Aged , Precision Medicine , Prognosis , Receptor, ErbB-2/metabolism , Retrospective Studies , Young Adult
5.
Biol Pharm Bull ; 43(4): 663-668, 2020.
Article in English | MEDLINE | ID: mdl-32238707

ABSTRACT

Hypersensitivity reactions, including anaphylaxis, are common side effects associated with docetaxel treatment in breast cancer patients. However, preventive measures have not yet been established. In this study, we retrospectively analyzed the risk factors for developing anaphylaxis in 182 female breast cancer patients treated with docetaxel. We found that 6.6% of all patients (n = 12) experienced anaphylaxis. Multivariate analyses indicated that concentration of docetaxel higher than 0.275 mg/m2/mL, docetaxel dose rate higher than 1.15 mg/m2/min, and white blood cell count less than 4290 cells/mL are risk factors for developing docetaxel-related anaphylaxis. In particular, concentrations of docetaxel or doses per administration time were associated with a high odds ratio (11.88 or 11.60) for docetaxel-related anaphylaxis. Moreover, patients receiving doses in 250 mL volume experienced anaphylaxis more frequently than those receiving doses in 500 mL (7.0 vs. 0.9%, p = 0.0236). Additionally, patients receiving treatments over 60 min tended to experience anaphylaxis more frequently than those who were treated over 90 min (6.7 vs. 1.1%, p = 0.0637). The present results indicate that high docetaxel concentrations, high dose rates, and low white blood cell counts are risk factors for developing docetaxel-related anaphylaxis, and administering docetaxel diluted in 500 mL over 90 min may limit docetaxel-induced hypersensitivity reactions.


Subject(s)
Anaphylaxis/chemically induced , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Breast Neoplasms/drug therapy , Docetaxel/administration & dosage , Docetaxel/adverse effects , Drug Hypersensitivity/etiology , Administration, Intravenous , Adult , Aged , Anaphylaxis/immunology , Breast Neoplasms/immunology , Drug Administration Schedule , Drug Hypersensitivity/immunology , Female , Humans , Incidence , Leukocyte Count , Middle Aged , Risk Factors
6.
Breast Cancer ; 26(1): 47-57, 2019 Jan.
Article in English | MEDLINE | ID: mdl-29971631

ABSTRACT

BACKGROUND: Neoadjuvant chemotherapy (NAC) is the standard therapeutic strategy for triple-negative breast cancer (TNBC). TNBC patients with residual disease after NAC have a significantly worse survival than those with pathological complete response (pCR); however, there is no apparent prognostic factor for non-pCR patients. Cancer stemness or epithelial-mesenchymal transition (EMT) might influence the sensitivity to chemotherapy. PATIENTS AND METHODS: Forty-eight patients with TNBC who were treated with NAC were available were included in this study. The expressions of stemness marker CD44v9, EMT marker vimentin and BRCA1, and basal phenotype were evaluated with immunohistochemistry. The relationships between the expression of these proteins and the pCR rate and the prognosis, especially in the patients with residual tumors, were investigated. RESULTS: Among the 48 patients, pCR was achieved in 14 cases. High nuclear grade and basal phenotype in the pre-NAC samples were significantly correlated with pCR (p = 0.0458 and 0.0343). There were no significant relationships between the pCR rate and the expression of CD44v9, vimentin, or BRCA1. Achieving pCR was significantly correlated with longer distant metastasis-free survival (DMFS) (p = 0.0206). High CD44v9 expression was significantly associated with shorter DMFS (p = 0.0291). Among the patients in whom pCR was not achieved, high grade in the residual tumor cells, poor pathological response and high CD44v9 expression in the pre-treatment CNB samples were significantly correlated with a poor DMFS (p = 0.0433, 0.0406 and p = 0.0333). In addition, high grade in the residual tumor cells was significantly associated with high CD44v9 expression in the pre-treatment CNB (p = 0.0389). CONCLUSIONS: High CD44v9 expression in pre-NAC samples was associated with poor prognosis in TNBC patients treated with NAC, especially for those in whom pCR was not achieved.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/metabolism , Hyaluronan Receptors/metabolism , Triple Negative Breast Neoplasms/pathology , Adult , Aged , BRCA1 Protein/metabolism , Breast/pathology , Breast/surgery , Disease-Free Survival , Female , Humans , Mastectomy , Middle Aged , Neoadjuvant Therapy/methods , Neoplasm, Residual , Prognosis , Protein Isoforms/metabolism , Triple Negative Breast Neoplasms/therapy , Vimentin/metabolism
7.
Anticancer Res ; 38(3): 1579-1584, 2018 03.
Article in English | MEDLINE | ID: mdl-29491088

ABSTRACT

BACKGROUND: Previous studies have suggested that the presence of visceral metastasis is a parameter useful in predicting the treatment efficacy of fulvestrant in patients with advanced breast cancer. PATIENTS AND METHODS: We retrospectively examined the association between treatment efficacy and presence of visceral metastasis in 75 patients with hormone receptor-positive recurrent breast cancer who were treated with fulvestrant or no more than five lines of other endocrine monotherapy after recurrence. RESULTS: Nineteen patients received fulvestrant, 10 of whom had visceral metastasis. The median time to progression was 4 months for the overall study population; it was significantly longer for patients with non-visceral metastasis (5.4 months; 95% confidence interval=3.7-11.2 months) than for those with visceral metastasis (3.3 months; 95% confidence interval, 0.4-5.3 months; p=0.01). No differences in time to progression were found between the groups of patients with visceral metastasis and non-visceral metastasis who underwent other endocrine therapies. CONCLUSION: Fulvestrant is more effective for patients with non-visceral metastasis of recurrent breast cancer with than for those with visceral metastasis.


Subject(s)
Breast Neoplasms/drug therapy , Estradiol/analogs & derivatives , Receptors, Steroid/metabolism , Viscera/pathology , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Disease-Free Survival , Estradiol/therapeutic use , Female , Fulvestrant , Humans , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local , Treatment Outcome
8.
Breast Cancer ; 24(5): 714-719, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28243992

ABSTRACT

BACKGROUND: For premenopausal women with breast cancer, information on the effects of chemotherapy and the risk of infertility is important. In this study, the effect of chemotherapy on the ovarian function in premenopausal women with hormone receptor-positive breast cancer was investigated, with an age-stratified analysis of the appearance of amenorrhea and the resumption of menstruation after the use of chemotherapy with anthracyclines or taxanes. PATIENTS AND METHODS: Premenopausal women diagnosed with operable Stage I-III hormone receptor-positive breast cancer and underwent neoadjuvant or adjuvant chemotherapy with the standard regimen of anthracyclines and/or taxanes were included. The patients were classified into age groups in 5-year increments, and the rates of chemotherapy-induced amenorrhea (CIA), resumption of menstruation, and duration of CIA after chemotherapy were analyzed. RESULTS: The subjects consisted of 101 patients (median age 45 years). CIA occurred in 97 (96%) patients and 40 patients resumed menstruation. In all patients aged ≤39 years menstruation restarted, whereas in all patients aged ≥50 years, menstruation did not restart. For the patients who resumed menstruation, the younger the patients, the sooner menstruation tended to restart. The resumption of menstruation occurred within 1 year for younger patients aged around 30 years, but for those aged ≥35 years, 60% of cases took around 2-3 years for resumption. CONCLUSIONS: The incidence of CIA, the resumption of menstruation and duration of CIA after chemotherapy depend greatly on the patient's age.


Subject(s)
Amenorrhea/epidemiology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Menstruation/drug effects , Premenopause/drug effects , Adult , Age Factors , Amenorrhea/chemically induced , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Chemotherapy, Adjuvant/adverse effects , Chemotherapy, Adjuvant/methods , Female , Humans , Incidence , Middle Aged , Neoadjuvant Therapy/adverse effects , Neoadjuvant Therapy/methods , Ovary/drug effects , Ovary/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Time Factors , Young Adult
9.
Breast Cancer ; 24(6): 733-741, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28316008

ABSTRACT

BACKGROUND: Squamous cell carcinoma (SCC) of the breast is a rare and generally aggressive disease that accounts for less than 0.1% of all breast carcinomas. Although SCCs have distinct morphological features, their origin and cytogenetic profile are not well understood. METHODS: Five patients with SCC were studied. The tumor area that was predominantly composed of SCC components was macrodissected and DNA was extracted. In three cases, an invasive or noninvasive ductal carcinoma of no special type (NST) component was also present. NST-component DNA was also extracted. The tumor DNA was used for array comparative genomic hybridization analysis using a high-density oligonucleotide microarray. The cytogenetic profile of the SCC components was compared with each other and with the paired NST component in three of the five cases. RESULTS: The cytogenetic profile of the SCC components indicated large intertumoral heterogeneity. There were between 2 and 160 copy number alterations per case, and no common copy number alterations were identified. The cytogenetic profiles of the paired SCC and NST components were similar but not identical. Although, in one case, a larger number of copy number aberrant regions were detected in the SCC component than the NST component. In this case, all the NST component aberrations were present in the SCC component. This implies that the SCC component originated from the NST component. There were no common SCC component-specific aberrations in the three NST-component cases. CONCLUSION: Our results demonstrate the cytogenetic inter- and intratumoral heterogeneity of SCC of the breast. Our comparison of cytogenetic profiles indicated that the SCC component originated from the NST component in one case.


Subject(s)
Breast Neoplasms/genetics , Carcinoma, Ductal, Breast/genetics , Carcinoma, Squamous Cell/genetics , Chromosome Aberrations , Aged , Breast/pathology , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Carcinoma, Squamous Cell/pathology , Comparative Genomic Hybridization , Cytogenetic Analysis/methods , DNA Copy Number Variations/genetics , Female , Humans , Mastectomy , Middle Aged , Oligonucleotide Array Sequence Analysis , Sentinel Lymph Node Biopsy
10.
PLoS One ; 11(12): e0168090, 2016.
Article in English | MEDLINE | ID: mdl-27977754

ABSTRACT

Recent studies have identified the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3B (APOBEC3B) as a source of mutations in various malignancies. APOBEC3B is overexpressed in several human cancer types, including breast cancer. In this study, we analyzed APOBEC3B mRNA expression in 305 primary breast cancers of Japanese women using quantitative reverse transcription-PCR, and investigated the relationships between the APOBEC3B mRNA expression and clinicopathological characteristics, prognosis, and TP53 mutations. The expression of APOBEC3B mRNA was detected in 277 tumors and not detected in 28 tumors. High APOBEC3B mRNA expression was significantly correlated with ER- and PR-negativity, high grade and high Ki67 index. The APOBEC3B mRNA expression was highest in the triple-negative and lowest in the hormone receptor-positive/HER2-negative subtypes. The TP53 gene was more frequently mutated in the tumors with high APOBEC3B mRNA expression. High APOBEC3B mRNA expression was significantly associated with poor recurrence-free survival in all cases and the ER-positive cases. These findings were almost consistent with the previous reports from the Western countries. In conclusion, high APOBEC3B mRNA expression was related to the aggressive phenotypes of breast cancer, high frequency of TP53 mutation and poor prognosis, especially in ER-positive tumors.


Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cytidine Deaminase/genetics , Minor Histocompatibility Antigens/genetics , RNA, Messenger/genetics , Asian People/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , Polymerase Chain Reaction , Polymorphism, Single Nucleotide/genetics , Tumor Suppressor Protein p53/genetics
11.
Sci Rep ; 6: 27525, 2016 06 09.
Article in English | MEDLINE | ID: mdl-27277343

ABSTRACT

Sentinel lymph node biopsy is performed as a standard procedure in breast cancer surgery, and the development of quick and simple methods to detect metastatic lesions is in high demand. Here, we validated a new fluorescent method using γ-glutamyl hydroxymethyl rhodamine green to diagnose metastatic lymph nodes in breast cancer. One hundred and forty-nine lymph nodes from 38 breast cancer patients were evaluated in this study. Comparison of fluorescent and pathological images showed that this fluorescent method was successful for visualizing breast cancer cells in lymph nodes. This method had a sufficiently high sensitivity (97%), specificity (79%) and negative predictive value (99%) to render it useful for an intraoperative diagnosis of cancer. These preliminary findings suggest that this novel method is useful for distinguishing non-cancerous specimens from those in need of careful examination and could help save time and cost for surgeons and pathologists.


Subject(s)
Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Dipeptides/chemistry , Lymphatic Metastasis/diagnostic imaging , Rhodamines/chemistry , Aged , Carcinoma, Lobular/pathology , Female , Humans , Lymph Nodes/pathology , Microscopy, Fluorescence , Middle Aged , Neoplasm Metastasis , Sensitivity and Specificity , Sentinel Lymph Node Biopsy
12.
Sci Rep ; 5: 12080, 2015 Jul 13.
Article in English | MEDLINE | ID: mdl-26165706

ABSTRACT

We previously developed γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) as a tool to detect viable cancer cells, based on the fact that the enzyme γ-glutamyltranspeptidase (GGT) is overexpressed on membranes of various cancer cells, but is not expressed in normal tissue. Cleavage of the probe by GGT generates green fluorescence. Here, we examined the feasibility of clinical application of gGlu-HMRG during breast-conserving surgery. We found that fluorescence derived from cleavage of gGlu-HMRG allowed easy discrimination of breast tumors, even those smaller than 1 mm in size, from normal mammary gland tissues, with 92% sensitivity and 94% specificity, within only 5 min after application. We believe this rapid, low-cost method represents a breakthrough in intraoperative margin assessment during breast-conserving surgery.


Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/pathology , Breast/pathology , Fluorescent Dyes/metabolism , Rhodamines/metabolism , gamma-Glutamyltransferase/metabolism , Breast/metabolism , Breast Neoplasms/metabolism , Cell Line, Tumor , Female , Humans , MCF-7 Cells , Sensitivity and Specificity
13.
Clin Breast Cancer ; 15(6): 498-504, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26195437

ABSTRACT

BACKGROUND: Triple-negative breast cancer (TNBC) has many similarities with basal-like breast cancer. Additionally, TNBCs are associated with Breast cancer susceptibility gene I (BRCA1) functional loss, which leads to impaired homologous recombination-mediated DNA repair. Although somatic mutations in BRCA1 rarely occur in sporadic breast cancer, lower than normal rates of expression of BRCA1 is reported to be an important factor that contributes to tumorigenesis in sporadic tumors. The epigenetic inactivation of BRCA1 expression might thus play an important role in sporadic breast cancer cases. PATIENTS AND METHODS: Breast cancer specimens were obtained from 69 TNBC and 161 non-TNBC patients who underwent surgery without neoadjuvant systemic therapy. BRCA1 promoter methylation status was investigated using combined bisulfite and restriction analysis. BRCA1 mRNA expression was evaluated using quantitative reverse transcriptase polymerase chain reaction and BRCA1 protein expression was assessed using immunohistochemistry. RESULTS: BRCA1 promoter methylation was found in 11 tumors and all of these were in TNBC cases (P < .0001). BRCA1 promoter methylation was significantly associated with lymphovessel invasion (P = .02), high nuclear grade (P = .05), low BRCA1 mRNA expression (P < .0001), and loss of BRCA1 protein expression (P = .0015). BRCA1 promoter methylation was significantly associated with shorter overall survival (P = .038). CONCLUSION: BRCA1 promotor methylation was found only in TNBC cases and the methylated cases account for 16% of TNBC. BRCA1 promoter methylation was significantly associated with reduced BRCA1 expression, aggressive phenotype, and poor prognosis. BRCA1 promoter methylation is an important mechanism that leads to functional loss of BRCA1.


Subject(s)
BRCA1 Protein/genetics , DNA Methylation/genetics , Epigenesis, Genetic/genetics , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology , Adult , Aged , Aged, 80 and over , BRCA1 Protein/biosynthesis , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Middle Aged , Neoplasm Invasiveness , Promoter Regions, Genetic/genetics , Proportional Hazards Models , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction
14.
Mol Clin Oncol ; 3(4): 919-923, 2015 Jul.
Article in English | MEDLINE | ID: mdl-26171207

ABSTRACT

MicroRNA-29b (miR-29b) targets numerous important genes that mediate carcinogenesis and tumor development in breast cancer in vitro and in vivo. The aim of the present study was to determine the clinical significance of miR-29b expression in primary breast cancer patients. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) of miR-29b and certain target genes of miR-29b, such as DNA methyltransferase 3A (DNMT3A), ten-eleven translocation 1 (TET1) and thymine DNA glycosylase (TDG), was performed in 94 primary breast cancer samples. Low expression of miR-29b in primary tumors was significantly associated with poorer disease-free survival (DFS) (P=0.0075) and overall survival (OS) (p=0.0012). Multivariate analysis indicated that miR-29b expression was an independent prognostic factor for OS [relative risk=15.6 (2.33-348), P=0.0026]. In addition, a significant inverse correlation was identified between the expression levels of DNMT3A and miR-29b in estrogen receptor-positive breast cancer patients (P=0.027). To the best of our knowledge, this is the first study to investigate the clinicopathological significance of miR-29b in breast cancer cases and miR-29b is shown to act as a tumor suppressive microRNA in breast cancer and as a potential marker for recurrence and metastasis in breast cancer patients.

15.
J Clin Invest ; 125(2): 621-35, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25555218

ABSTRACT

The gene encoding F-box protein FBXW7 is frequently mutated in many human cancers. Although most previous studies have focused on the tumor-suppressive capacity of FBXW7 in tumor cells themselves, we determined that FBXW7 in the host microenvironment also suppresses cancer metastasis. Deletion of Fbxw7 in murine BM-derived stromal cells induced accumulation of NOTCH and consequent transcriptional activation of Ccl2. FBXW7-deficient mice exhibited increased serum levels of the chemokine CCL2, which resulted in the recruitment of both monocytic myeloid-derived suppressor cells and macrophages, thereby promoting metastatic tumor growth. Administration of a CCL2 receptor antagonist blocked the enhancement of metastasis in FBXW7-deficient mice. Furthermore, in human breast cancer patients, FBXW7 expression in peripheral blood was associated with serum CCL2 concentration and disease prognosis. Together, these results suggest that FBXW7 antagonizes cancer development in not only a cell-autonomous manner, but also a non-cell-autonomous manner, and that modulation of the FBXW7/NOTCH/CCL2 axis may provide a potential approach to suppression of cancer metastasis.


Subject(s)
Breast Neoplasms/metabolism , Cell Cycle Proteins/biosynthesis , F-Box Proteins/biosynthesis , Gene Expression Regulation, Neoplastic , Mammary Neoplasms, Experimental/metabolism , Neoplasm Proteins/biosynthesis , Ubiquitin-Protein Ligases/biosynthesis , Animals , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast Neoplasms/therapy , CD2 Antigens/genetics , CD2 Antigens/metabolism , Cell Cycle Proteins/genetics , Cell Line, Tumor , Chemokine CCL2/genetics , Chemokine CCL2/metabolism , F-Box Proteins/genetics , F-Box-WD Repeat-Containing Protein 7 , Female , Humans , Macrophages/metabolism , Macrophages/pathology , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/pathology , Mammary Neoplasms, Experimental/therapy , Mice , Mice, Transgenic , Neoplasm Metastasis , Neoplasm Proteins/genetics , Receptors, Notch/genetics , Receptors, Notch/metabolism , Retrospective Studies , Stromal Cells/metabolism , Stromal Cells/pathology , Ubiquitin-Protein Ligases/genetics
16.
Anticancer Res ; 35(1): 123-7, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25550542

ABSTRACT

BACKGROUND/AIM: MiR-15a targets Cyclin E1 (CCNE1), which regulates the cell cycle and promotes cell proliferation and progression. Herein, we investigated the clinicopathological significance of miR-15a as a prognostic marker in breast cancer (BC) cases. MATERIALS AND METHODS: We collected primary tumor samples of 230 BC cases, including 68 triple-negative cases. The expression levels of miR-15a in primary tumors were measured by qRT-PCR assay. RESULTS: Low expression of miR-15a in primary tumors was significantly correlated with shorter disease-free survival (p=0.0012) and overall survival (p=0.005) compared to the high miR-15a expression in triple-negative BC cases. Multivariate analysis indicated that low miR-15a expression was an independent prognostic factor for overall survival [RR=2.56(1.03-7.18), p=0.04]. CONCLUSION: MiR-15a expression levels could be a promising biological and prognostic marker for overall survival especially in triple-negative BC cases.


Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , MicroRNAs/metabolism , Adult , Aged , Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Female , Gene Expression , Humans , Kaplan-Meier Estimate , MicroRNAs/genetics , Middle Aged , Multivariate Analysis , Prognosis , Proportional Hazards Models
17.
Breast Cancer ; 22(5): 520-8, 2015 Sep.
Article in English | MEDLINE | ID: mdl-24415069

ABSTRACT

BACKGROUND: Determining the indications for adjuvant chemotherapy (CT) in patients with hormone receptor (HR)-positive/HER2-negative breast cancer are difficult. The transcription factors GATA-binding protein 3 (GATA-3) and Forkhead-box protein A1 (FOXA1) are crucial for the hormone responsive phenotype of breast cancer. This study evaluated whether the expression of GATA-3 and FOXA1 is a prognostic and predictive marker of outcomes in patients with HR-positive/HER2-negative breast cancer. METHODS: The expression of GATA-3 and FOXA1 was analyzed immunohistochemically in 214 patients with invasive breast cancer to evaluate the association with the clinicopathological features and the prognosis. RESULTS: GATA-3 expression was positively correlated with FOXA1 expression (P < 0.0001). Both GATA-3 and FOXA1 were positively correlated with ER (P < 0.0001 each) and PR expression (P = 0.0001 and P = 0.0009, respectively), and inversely correlated with nuclear grade (P = 0.0002 and P = 0.0018, respectively) and Ki67 index (P = 0.0052 and P = 0.0049, respectively). Expression of GATA-3 and FOXA1 was associated with better prognosis. FOXA1 was an independent favorable prognostic marker in HR-positive/HER2-negative breast cancer. Disease-free survival rates were similar in patients with HR-positive/HER2-negative breast cancer and high FOXA1 expression given adjuvant hormone therapy (HT) alone and those given CT plus HT. CONCLUSION: GATA-3 and FOXA1 are associated with a less aggressive phenotype and a better prognosis in patients with HR-positive/HER2-negative breast cancer. FOXA1 may be useful in identifying those patients who may not require adjuvant CT.


Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , GATA3 Transcription Factor/metabolism , Hepatocyte Nuclear Factor 3-alpha/metabolism , Receptor, ErbB-2/metabolism , Biomarkers, Tumor/metabolism , Breast Neoplasms/mortality , Breast Neoplasms/therapy , Chemotherapy, Adjuvant , Disease-Free Survival , Female , Humans , Ki-67 Antigen/metabolism , Lymphatic Metastasis/pathology , Middle Aged , Prognosis , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Treatment Outcome
18.
World J Surg Oncol ; 12: 84, 2014 Apr 04.
Article in English | MEDLINE | ID: mdl-24708742

ABSTRACT

We herein report a case of invasive micropapillary carcinoma (IMPC) involving extensive lymph node metastasis with no recurrence for over 7 years. A 41-year-old female presented with pain and a swelling mass in the left axillary region, which had been present for several months. The tumor measured 1.6 cm in diameter in the middle of upper area of the left breast. Based on the findings of a core needle biopsy the pathological diagnosis was IMPC or mucinous carcinoma. The cytology of the left axillary lymph node was positive for metastatic carcinoma. The patient underwent a left mastectomy and a left axillary dissection (level I to III). The postoperative pathological diagnosis was IMPC with mucin production, and the number of metastatic lymph nodes was 59. The patient was given adjuvant chemotherapy (four courses of 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and four courses of docetaxel), radiation for the left chest wall, supraclavicular and internal thoracic area, and then received tamoxifen for 5 years. The patient has remained recurrence-free for over 7 years. IMPC is known to be an aggressive histological type associated with a high incidence of lymph node metastasis and a poor prognosis. It seems that long-term survival was obtained by performing sufficient medical treatment. Prognostic factors other than the number of lymph node metastases may also exist.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/pathology , Carcinoma, Papillary/secondary , Adult , Breast Neoplasms/therapy , Carcinoma, Papillary/therapy , Combined Modality Therapy , Female , Humans , Lymphatic Metastasis , Neoplasm Invasiveness , Prognosis , Radiotherapy
19.
Surg Today ; 44(9): 1678-84, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24218007

ABSTRACT

PURPOSE: The aim of the current study was to explore the efficacy and safety of combination therapy using a luteinizing hormone-releasing hormone (LHRH) agonist plus an aromatase inhibitor (AI) as second-line therapy in premenopausal females with hormone receptor (HR)-positive recurrent or metastatic breast cancer (MBC). METHODS: A retrospective analysis was conducted in patients registered in the breast cancer database of our institution between January 2001 and December 2012. The breast cancer database identified 14 premenopausal patients who had been treated with an LHRH agonist plus AI for HR-positive recurrent or MBC. RESULTS: Fourteen patients with recurrent breast cancer (N = 10) or metastatic disease at primary diagnosis (N = 4) were included in the present study. All patients had previously been treated with an LHRH agonist plus tamoxifen. The clinical benefit rate was 71.4% and the median TTP was 11 months (95% confidence interval 1.7-20.3 months). One patient discontinued treatment because of liver dysfunction (grade 3). CONCLUSIONS: The combination of an LHRH agonist plus an AI is a treatment option for premenopausal females with HR-positive MBC that can prolong the chemotherapy-free interval and yield effective disease stabilization.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Aromatase Inhibitors/administration & dosage , Breast Neoplasms/drug therapy , Gonadotropin-Releasing Hormone/agonists , Premenopause , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Tamoxifen/administration & dosage , Adult , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local , Retrospective Studies , Treatment Outcome
20.
Breast Cancer ; 21(3): 341-9, 2014 May.
Article in English | MEDLINE | ID: mdl-22903204

ABSTRACT

BACKGROUND: Metadherin (MTDH) plays functional roles in the tumorigenesis and tumor progression of various cancers. This study investigated the associations between MTDH and the clinicopathological features in primary breast carcinomas to clarify the role of MTDH in the phenotypes and prognosis of breast cancer. METHODS: A total of 195 primary invasive breast cancer samples were evaluated. The MTDH DNA copy number and MTDH mRNA expression were analyzed by quantitative genomic polymerase chain reaction (PCR) and quantitative reverse transcriptase PCR. MTDH protein expression was analyzed by immunohistochemistry. RESULTS: A positive correlation was found between the expression of MTDH protein and mRNA expression and the MTDH DNA copy number. MTDH overexpression was significantly associated with a high nuclear grade, negative estrogen receptor (ER) and progesterone receptor (PR) expression, high Ki67 index, poor disease-free survival (P = 0.0001), poor distant metastasis-free survival (P = 0.009), and poor overall survival (P = 0.0101). MTDH overexpression showed a particularly negative impact on the prognosis in node-negative patients. A multivariate analysis showed MTDH overexpression to be independently associated with a poor disease-free survival rate [HR 3.45, 95 % confidence interval (CI) 1.69-6.84, P = 0.0010] and a poor distant metastasis-free survival rate (HR 2.39, 95 % CI 1.08-5.01, P = 0.0319). CONCLUSION: MTDH overexpression contributes to an aggressive phenotype, thus leading to a poor prognosis for primary invasive breast cancer.


Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Adult , Asian People , Breast Neoplasms/genetics , Breast Neoplasms/mortality , Disease-Free Survival , Female , Gene Dosage , Gene Expression Regulation, Neoplastic , Humans , Membrane Proteins , Middle Aged , Prognosis , RNA-Binding Proteins
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