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[Background] Many of the tripartite motif (TRIM) proteins, like Efp/TRIM25 which was identified by our group previously (Nature 417, 871-875, 2002), function as E3 ubiquitin ligases, and are thought to be involved in various physiological and pathological processes such as immunity and oncogenesis. In regard to tripartite motif containing 44 (TRIM44), which is an atypical TRIM family protein lacking RING finger domain, some evidences suggest that it is implicated in the progression of several human malignancies. But its pathophysiological significance in breast cancer remains unknown. [Methods] In the present study, immunohistochemical analysis using anti-TRIM44 antibody was performed in clinical breast cancer tissues from 129 patients with the approval of institutional ethical committees (approval number: 845). We then explored the pathophysiological role of TRIM44 in breast cancer by modulating TRIM44 expression in MCF-7 and MDA-MB-231 breast cancer cells. [Results] TRIM44 strong immunoreactivity was significantly associated with nuclear grade, distant disease-free survival and overall survival of the breast cancer patients. With multivariate analysis it was shown that the TRIM44 status was an independent prognostic factor for distant disease-free survival and overall survival. The proliferation of MCF-7 and MDA-MB-231 cells was significantly decreased by siRNA-mediated TRIM44 knockdown. TRIM44 knockdown also suppressed migration of MDA-MB-231 cells. Microarray analysis and qRT-PCR revealed that TRIM44 knockdown upregulated CDK19 (Cyclin Dependent Kinase 19), which is reported to be a tumor suppressor gene, whereas downregulated MMP1 (Matrix Metallopeptidase 1) in MDA-MB-231 cells. Notably, TRIM44 knockdown impaired nuclear factor-kappa B (NF-κB)-mediated transcriptional activity stimulated by tumor necrosis factor α (TNFα). Moreover, TRIM44 knockdown substantially attenuated the TNFα-dependent phosphorylation of p65 subunit of NF-κB and IκBα in both MCF-7 and MDA-MB-231 cells. [Discussion] Our clinical study showed that prognosis of breast cancer patients is correlated with the immunoreactivity detected by anti-TRIM44 antibody. This result suggested that expression of TRIM44 protein could be used as a potential biomarker of breast cancer. We demonstrated that NF-κB signaling pathway is modulated by TRIM44. Since NF-κB augmentation is shown to be related to aggressive character of breast cancer, stimulation of NF-κB signaling with TRIM44 might be underlying mechanism of poor prognosis. Our in vitro study showed TRIM44 knockdown caused attenuated proliferation and migration of breast cancer cells, raising the possibility of TRIM44 as a potential therapeutic target for breast cancer. These findings provide new clues to develop alternative effective strategies for breast cancer management. Citation Format: Kawabata H, Azuma K, Ikeda K, Sugitani I, Kinowaki K, Fujii T, Osaki A, Saeki T, Horie-Inoue K, Inoue S. TRIM44 is a possible poor prognostic factor for breast cancer patients and positively regulates NF-κB signaling pathway [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-07-06.

Our group and others have previously reported that a fibrotic focus is a very useful histological factor for the accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast. We classified 258 cases of invasive ductal carcinoma into those with and those without a fibrotic focus to investigate whether the presence of a fibrotic focus was significantly associated with the degree of tumor-associated macrophage (CD68, CD163 or CD204-positive) infiltration or whether the presence of tumor-associated macrophage infiltration heightened the malignant potential of invasive ductal carcinoma with a fibrotic focus. Multiple regression analyses demonstrated that a fibrotic focus was the only factor that was significantly associated with a high level of CD68-, CD163- or CD204-positive tumor-associated macrophage infiltration. The combined assessment of the presence or absence of a fibrotic focus and a high or a low level of CD204-positive tumor-associated macrophage infiltration clearly demonstrated that CD204-positive tumor-associated macrophage infiltration had a significant prognostic power only for patients with invasive ductal carcinoma with a fibrotic focus in multivariate analyses; CD204-positive tumor-associated macrophages might only exert a significant effect on tumor progression when a fibrotic focus is present within the invasive ductal carcinoma of the breast.

Background This phase II neoadjuvant study evaluated the efficacy and safety of a triweekly regimen of docetaxel and carboplatin in combination with trastuzumab (TCbH) in Japanese women with human epidermal growth factor receptor type2 (HER2)-positive primary breast cancer. Methods Patients with HER2-positive, stage I–III invasive breast cancer received six courses of trastuzumab (8 mg/kg loading dose, then 6 mg/kg, day 1), docetaxel (75 mg/m2, day 1), and carboplatin (area under the curve: 6, day 1) every 3 weeks. The primary endpoint was pathological complete response (pCR) of both breast and axillary lymph node disease. Results Fifty patients were enrolled in this study. Median age was 58 (range 32–75) years. All patients underwent definitive surgery. Thirty-three (66%) patients completed the chemotherapy course, while the treatment was delayed or discontinued in the other 17 (34%) patients because of adverse events (AEs). The pCR rate was 52%; the overall response rate was 66%. Grade 3/4 AEs due to nonhematological toxicity were anorexia (4%), diarrhea (2%), and rash (2%), and those due to hematological toxicity were neutropenia (36%), anemia (12%), and thrombocytopenia (2%). Conclusion Although the triweekly six-course regimen of TCbH achieved a high pCR rate, hematological AEs frequently occurred during the latter part of the chemotherapy course. One-third of patients experienced delayed or discontinued chemotherapy. Clinical registration number: http://www.umin.org.auUMIN000013513.

Hypoxia is a key driver of cancer progression. We evaluated the prognostic impact ofForty-four patients with stage II/III primary breast cancer underwent positron emission tomography/computed withTumors with higher nuclear grade and negativities of estrogen receptor (ER) and progesterone receptor had significantly higher FMISO-TBR than other tumors. Kaplan-Meier survival curves showed that patients with a higher FMISO-TBR (cutoff, 1.48) had a poorer prognosis of DFS (p = 0.0007) and OS (p = 0.04) than those with a lower FMISO-TBR. Multivariate analysis indicated that higher FMISO-TBR and ER negativity were independent predictors of shorter DFS (p = 0.01 and 0.03). Higher FMISO-TBR was associated with higher plasma levels of angiogenic hypoxic markers such as vascular endothelial growth factor, transforming growth factor-α, and interleukin 8.FMISO-PET/CT is useful for assessing the prognosis of patients with breast cancer, but it should be stratified by ER status.UMIN Clinical Trials Registry, UMIN000006802 . Registered on 1 December 2011.

Background Hypoxia is a key driver of cancer progression. We evaluated the prognostic impact of 18F-fluoromisonidazole (FMISO) prior to treatment in patients with breast cancer. Methods Forty-four patients with stage II/III primary breast cancer underwent positron emission tomography/computed with 18F-fluorodeoxyglucose (FDG-PET/CT) and FMISO. After measurement by FDG-PET/CT, the tissue-to-blood ratio (TBR) was obtained using FMISO-PET/CT. FMISO-TBR was compared for correlation with clinicopathological factors, disease-free survival (DFS), and overall survival (OS). Multiplex cytokines were analyzed for the correlation of FMISO-TBR. Results Tumors with higher nuclear grade and negativities of estrogen receptor (ER) and progesterone receptor had significantly higher FMISO-TBR than other tumors. Kaplan-Meier survival curves showed that patients with a higher FMISO-TBR (cutoff, 1.48) had a poorer prognosis of DFS (p = 0.0007) and OS (p = 0.04) than those with a lower FMISO-TBR. Multivariate analysis indicated that higher FMISO-TBR and ER negativity were independent predictors of shorter DFS (p = 0.01 and 0.03). Higher FMISO-TBR was associated with higher plasma levels of angiogenic hypoxic markers such as vascular endothelial growth factor, transforming growth factor-α, and interleukin 8. Conclusions FMISO-PET/CT is useful for assessing the prognosis of patients with breast cancer, but it should be stratified by ER status. Trial registration UMIN Clinical Trials Registry, UMIN000006802. Registered on 1 December 2011. Electronic supplementary material The online version of this article (10.1186/s13058-018-0970-6) contains supplementary material, which is available to authorized users.

Many of the tripartite motif (TRIM) proteins function as E3 ubiquitin ligases and are assumed to be involved in various events, including oncogenesis. In regard to tripartite motif-containing 44 (TRIM44), which is an atypical TRIM family protein lacking the RING finger domain, its pathophysiological significance in breast cancer remains unknown. We performed an immunohistochemical study of TRIM44 protein in clinical breast cancer tissues from 129 patients. The pathophysiological role of TRIM44 in breast cancer was assessed by modulating TRIM44 expression in MCF-7 and MDA-MB-231 breast cancer cells. TRIM44 strong immunoreactivity was significantly associated with nuclear grade (p = 0.033), distant disease-free survival (p = 0.031) and overall survival (p = 0.027). Multivariate analysis revealed that the TRIM44 status was an independent prognostic factor for distant disease-free survival (p = 0.005) and overall survival (p = 0.002) of patients. siRNA-mediated TRIM44 knockdown significantly decreased the proliferation of MCF-7 and MDA-MB-231 cells and inhibited the migration of MDA-MB-231 cells. Microarray analysis and qRT–PCR showed that TRIM44 knockdown upregulated CDK19 and downregulated MMP1 in MDA-MB-231 cells. Notably, TRIM44 knockdown impaired nuclear factor-kappa B (NF-κB)-mediated transcriptional activity stimulated by tumor necrosis factor α (TNFα). Moreover, TRIM44 knockdown substantially attenuated the TNFα-dependent phosphorylation of the p65 subunit of NF-κB and IκBα in both MCF-7 and MDA-MB-231 cells. TRIM44 would play a role in the progression of breast cancer by promoting cell proliferation and migration, as well as by enhancing NF-κB signaling.

Our group and others have previously reported that a fibrotic focus is a very useful histological factor for the accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast. We classified 258 cases of invasive ductal carcinoma into those with and those without a fibrotic focus to investigate whether the presence of a fibrotic focus was significantly associated with the degree of tumor-associated macrophage (CD68, CD163 or CD204-positive) infiltration or whether the presence of tumor-associated macrophage infiltration heightened the malignant potential of invasive ductal carcinoma with a fibrotic focus. Multiple regression analyses demonstrated that a fibrotic focus was the only factor that was significantly associated with a high level of CD68-, CD163- or CD204-positive tumor-associated macrophage infiltration. The combined assessment of the presence or absence of a fibrotic focus and a high or a low level of CD204-positive tumor-associated macrophage infiltration clearly demonstrated that CD204-positive tumor-associated macrophage infiltration had a significant prognostic power only for patients with invasive ductal carcinoma with a fibrotic focus in multivariate analyses; CD204-positive tumor-associated macrophages might only exert a significant effect on tumor progression when a fibrotic focus is present within the invasive ductal carcinoma of the breast.

Background Controversy surrounds the reliability of sentinel lymph node biopsy after primary systemic chemotherapy. In this study, we assessed axillary ultrasound for selecting patients most likely to optimally benefit from biopsy. Methods The study included 87 patients who received primary systemic chemotherapy and underwent a sentinel lymph node biopsy followed by axillary lymph node dissection. Lymph nodes >10 mm in diameter, irregularly swollen, round, and homogeneously hypoechoic without an echo-rich center were considered axillary ultrasound positive. Results In axillary ultrasound–negative patients before and after primary systemic chemotherapy, identification, sensitivity, and false-negative rates were 81%, 100%, and 0%, respectively. However, in patients whose lymph nodes converted from positive to negative after primary systemic chemotherapy, these values were 83%, 70.8%, and 29.2%, respectively. Conclusions Axillary ultrasound–negative patients before and after primary systemic chemotherapy were suitable for sentinel lymph node biopsy. Axillary ultrasound should be used during primary systemic chemotherapy and before surgery.

Background Advanced breast cancer patients have a higher risk of postoperative recurrence than early-stage breast cancer patients. Recurrence is believed to be caused by the increase in micrometases, which were not eradicated by preoperative or postoperative chemotherapy. Therefore, a new therapeutic strategy that can improve treatment efficacy is mandatory for advanced breast cancer. S-1 was shown to be effective and safe in Japanese metastatic breast cancer patients treated with previous chemotherapy, including anthracyclines. Thus, in this study, we evaluated S-1 as adjuvant chemotherapy in breast cancer patients after standard primary systemic chemotherapy. Methods The treatment consisted of 18 courses (a 2-week administration and a 1-week withdrawal; one year) administered at 80–120 mg/body/day. In cases judged to require postoperative radiotherapy, it was concurrently initiated on Day 1 of the study. If the estrogen receptor and/or human epidermal growth factor receptor 2 were positive, endocrine therapy and/or trastuzumab were permitted, concurrently. Results Of the 45 patients enrolled between September 2007 and September 2009 from 3 institutions, 43 patients were eligible. Thirty-two of the 43 (74.4%) patients received concurrent radiotherapy. Twenty-two of the 43 (51.2%) patients completed the scheduled courses of chemotherapy. The most common reasons for withdrawal of treatment were subjective symptoms, such as nausea, anorexia, or general fatigue during the first 9 courses of treatment in 9/43 (20.9%) patients, recurrence in 7/43 (16.3%) patients, and adverse events in 5/43 (11.6%) patients. The cumulative percentage of administration for 365 days was 66.4% (95% confidence interval: 50.8–79.1%). Although grade 3 neutropenia (9.3%), leukopenia (4.7%), and diarrhea (4.7%) were observed, they were manageable. No grade 4 adverse effects were observed. Conclusions The percentage of Japanese breast cancer patients completing the 18-course treatment and the cumulative percentage of administration for 365 days using S-1 after standard primary systemic chemotherapy were similar with the results of another study of adjuvant chemotherapy for the Japanese gastric cancer patients with no severe adverse effects. A phase III trial investigating the usefulness of adjuvant S-1 is now ongoing in Japan, and it is expected that S-1 will have a significant survival benefit in breast cancer patients. UMIN000013469.

Objective Nanoparticle albumin-bound paclitaxel (nab-PTX) is a solvent-free paclitaxel coupled to human albumin without an associated increase in toxicity. The neoadjuvant study of primary breast cancer was planned to evaluate tumor response and safety of triweekly nanoparticle albumin-bound paclitaxel. Methods Patients with Stage II/III HER2-negative primary breast cancer received four courses of nanoparticle albumin-bound paclitaxel 260 mg/m(2) every 3 weeks (q3w), followed by four courses of epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) q3w. Tumor response after nanoparticle albumin-bound paclitaxel was histologically evaluated. In addition, the clinical response, breast-conserving rate and safety of this treatment were monitored. Results Among 53 patients who received nanoparticle albumin-bound paclitaxel followed by epirubicin and cyclophosphamide neoadjuvant chemotherapy, pathological complete response and near-pathological complete response were confirmed in 3 (5.7%) and 7 (13.2%) patients who had surgery, respectively. The overall objective response rate was 71.7% after completion of chemotherapy. Based on Positron Emission Tomography Response Criteria in Solid Tumors using (18)F-fluorodeoxyglucose, complete metabolic response and partial metabolic response after 2-3 courses of nanoparticle albumin-bound paclitaxel were 15.1 and 52.8%, respectively. The most common significant toxicities of q3w nanoparticle albumin-bound paclitaxel were Grade 3 muscle pain, neuropathy and febrile neutropenia, each in 1 (1.9%) patient. There were no incidences of anaphylaxis or Grade 4/5 adverse events. Conclusion Neoadjuvant chemotherapy using q3w nanoparticle albumin-bound paclitaxel followed by epirubicin and cyclophosphamide was feasible in breast cancer patients with acceptable clinical response and drug tolerance, but conferred a low rate of pathological complete response. Monotherapy with q3w nanoparticle albumin-bound paclitaxel could be an appropriate substitute for solvent-based taxane in terms of therapeutic and safety management.

Aim: Treatment for breast cancer with collagen disorder is complicated due to the use of steroids and immunosuppressants, and its clinical course is thus interesting. We herein report the results of an investigation on breast cancer in women with collagen disorders. Methods: The subjects were 25 patients with collagen disorders among those diagnosed with breast cancer who had received treatment at our hospital from 2003 to 2011. We examined clinicopathological factors, treatment, recurrence-free survival rates and overall survival rates. Results: The mean age was 57 years (31-84 years), and the clinical stage was I in14 cases, II in 8, and III in 3. The status of lymph node metastasis was N0 in 15 cases and N1 in 10. Concomitant collagen disorders included rheumatoid arthritis in 11 cases, systemic lupus erythematosus in 4, dermatomyositis, mixed connective tissue disease, and Sjogren's syndrome in 2 cases each, and scleroderma and adult onset Still's disease in 1 case each. The status of hormone receptors (HR) and human epidermal growth factor 2 (HER2) expression was as follows: ER(+)HER2(-) in 18 cases (72.0%), HER(+)HER2(+) in 2 (8.0%), HR(-)HER2(+) in 1 (4.0%), triple negative in 4 (16.0%). While there was no bias in clinicopathological factors, 21 of the 25 cases (84.0%) had received steroids and/or immunosuppressants for collagen disorders. After a median observation period of 47 months, the recurrence-free survival and overall survival rate was 64.5% and 80.7%, respectively, lower than those of breast cancer patient who underwent surgery at approximately the same time (n = 476, recurrence-free survival rate: 85.3%, overall survival rate: 94.3%. Conclusions: In breast cancer cases with collagen disorders, steroids and/or other immunosuppressants were frequently administered, and both recurrence-free survival and overall survival rates were comparatively low. Disclosure: All authors have declared no conflicts of interest.