Prognostic impact of HER2-low positivity in patients with HR-positive, HER2-negative, node-positive early breast cancer.

Adjuvant therapy for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer (EBC) remains challenging. The prognostic significance of HER2-low positivity in these patients is not fully understood. In our retrospective study, we analyzed 647 patients with HR-positive, HER2-negative, node-positive EBC, stratifying them into three cohorts based on axillary lymph node involvement, tumor size, and characteristics. Cohort 1 included patients with either ≥ 4 positive axillary lymph nodes or 1-3 positive nodes with histological grade 3 or tumor size ≥ 5 cm. Cohort 2 consisted of patients with 1-3 positive nodes, histological grade < 3, tumor size < 5 cm, and Ki-67 ≥ 20%. Cohort 3 comprised patients with 1-3 positive nodes, histological grade < 3, tumor size < 5 cm, and Ki-67 < 20%. We compared invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) between HER2-low (IHC1+ or IHC2+/FISH-) and HER2-zero (IHC0) groups in each cohort. In cohort 1, HER2-low patients exhibited significantly better 5-year IDFS (84.2% vs. 73.6%, p = 0.0213) and DRFS (88.2% vs. 79.8%, p = 0.0154). However, no significant differences were observed in cohorts 2 and 3. Our findings suggest HER2-low positivity as a prognostic factor in HR-positive, HER2-negative, and node-positive EBC.

Assessment of nuclear grade-based recurrence risk classification in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive high-risk early breast cancer.

BACKGROUND: Histological grade (HG) has been used in the MonrachE trial to select patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive high-risk early breast cancer (EBC). Although nuclear grade (NG) is widely used in Japan, it is still unclear whether replacing HG with NG can appropriately select high-risk patients. METHODS: We retrospectively reviewed 647 patients with HR-positive, HER2-negative, node-positive EBC and classified them into the following four groups: group 1: ≥ 4 positive axillary lymph nodes (pALNs) or 1-3 pALNs and either grade 3 of both grading systems or tumors ≥ 5 cm; group 2: 1-3 pALNs, grade < 3, tumor < 5 cm, and Ki-67 ≥ 20%; group 3: 1-3 pALNs, grade < 3, tumor < 5 cm, and Ki-67 < 20%; and group 4: group 2 or 3 by HG classification but group 1 by NG classification. We compared invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) among the four groups using the Kaplan-Meier method with the log-rank test. RESULTS: Group 1 had a significantly worse 5-year IDFS and DRFS than groups 2 and 3 (IDFS 80.8% vs. 89.5%, P = 0.0319, 80.8% vs. 95.5%, P = 0.002; DRFS 85.2% vs. 95.3%, P = 0.0025, 85.2% vs. 98.4%, P < 0.001, respectively). Group 4 also had a significantly worse 5-year IDFS (78.0%) and DRFS (83.6%) than groups 2 and 3. CONCLUSIONS: NG was useful for stratifying the risk of recurrence in patients with HR-positive, HER2-negative, node-positive EBC and was the appropriate risk assessment for patient groups not considered high-risk by HG classification.

A prediction model for distant metastasis after isolated locoregional recurrence of breast cancer.

PURPOSE: The impact of progesterone receptor (PR) status on the prognosis of breast cancer after isolated locoregional recurrence (ILRR) remains unclear. This study evaluated the impact of clinicopathologic factors, including PR status of ILRR, on distant metastasis (DM) after ILRR. METHODS: We retrospectively identified 306 patients with ILRR diagnosed at the National Cancer Center Hospital between 1993 and 2021 from the database. Cox proportional hazards analysis was performed to examine factors associated with DM after ILRR. We developed a risk prediction model based on the number of detected risk factors and estimated survival curves using the Kaplan-Meier method. RESULTS: During a median follow-up time of 4.7 years after ILRR diagnosis, 86 patients developed DM, and 50 died. Multivariate analysis revealed that seven risk factors were associated with poor distant metastasis-free survival (DMFS): estrogen receptor-positive/PR-negative/human epidermal growth factor receptor 2-negative ILRR, short disease-free interval, recurrence site other than ipsilateral breast, no-resection of ILRR tumor, chemotherapy for the primary tumor, nodal stage in the primary tumor, and no endocrine therapy for ILRR. The predictive model classified patients into 4 groups based on the number of risk factors: low-, intermediate-, high-, and the highest-risk groups with 0 to 1, 2, 3 to 4, and 5 to 7 factors, respectively. This revealed significant variation in DMFS among the groups. A higher number of the risk factors was associated with poorer DMFS. CONCLUSION: Our prediction model, which considered the ILRR receptor status, may contribute to the development of a treatment strategy for ILRR.

Development and validation of a pre- and intra-operative scoring system that distinguishes between non-advanced and advanced axillary lymph node metastasis in breast cancer with positive sentinel lymph nodes: a retrospective study.

BACKGROUND: There are currently no scoring-type predictive models using only easily available pre- and intraoperative data developed for assessment of the risk of advanced axillary lymph node metastasis (ALNM) in patients with breast cancer with metastatic sentinel lymph nodes (SLNs). We aimed to develop and validate a scoring system using only pre- and intraoperative data to distinguish between non-advanced (≤ 3 lymph nodes) and advanced (> 3 lymph nodes) ALNM in patients with breast cancer with metastatic SLNs. METHODS: We retrospectively identified 804 patients with breast cancer (cT1-3cN0) who had metastatic SLNs and had undergone axillary lymph node dissection (ALND). We evaluated the risk factors for advanced ALNM using logistic regression analysis and developed and validated a scoring system for the prediction of ALNM using training (n = 501) and validation (n = 303) cohorts, respectively. The predictive performance was assessed using the receiver operating characteristic (ROC) curve, area under the curve (AUC), and calibration plots. RESULTS: Ultrasound findings of multiple suspicious lymph nodes, SLN macrometastasis, the ratio of metastatic SLNs to the total number of SLNs removed, and the number of metastatic SLNs were significant risk factors for advanced ALNM. Clinical tumor size and invasive lobular carcinoma were of borderline significance. The scoring system based on these six variables yielded high AUCs (0.90 [training] and 0.89 [validation]). The calibration plots of frequency compared to the predicted probability showed slopes of 1.00 (training) and 0.85 (validation), with goodness-of-fit for the model. When the cutoff score was set at 4, the negative predictive values (NPVs) of excluding patients with advanced ALNM were 96.8% (training) and 96.9% (validation). The AUC for predicting advanced ALNM using our scoring system was significantly higher than that predicted by a single independent predictor, such as the number of positive SLNs or the proportion of positive SLNs. Similarly, our scoring system also showed good discrimination and calibration ability when the analysis was restricted to patients with one or two SLN metastases. CONCLUSION: Our easy-to-use scoring system can exclude advanced ALNM with high NPVs. It may contribute to reducing the risk of undertreatment with adjuvant therapies in patients with metastatic SLNs, even if ALND is omitted.

Bone Marrow Carcinomatosis in a Stage IV Breast Cancer Patient Treated by Letrozole as First-Line Endocrine Therapy.

Bone marrow carcinomatosis (BMC) associated with breast cancer is a rare but often difficult-to-treat condition; we report a case of a female stage IV breast cancer patient in her seventies with BMC that improved with endocrine monotherapy. The patient had hemoglobinopenia and thrombocytopenia at the time of diagnosis. The diagnosis of BMC due to estrogen receptor-positive invasive lobular carcinoma was confirmed. After transfusion of 4 units of concentrated red blood cells, endocrine treatment with letrozole improved the hematopenia. Ten months after the treatment started, bone metastases worsened, so the patient was changed to combination therapy with palbociclib and fulvestrant, after which there was no worsening of the disease.

Spontaneous regression of breast lymphoproliferative disorders after withdrawal of methotrexate in rheumatoid arthritis patients with Epstein-Barr virus infection: a case report and review of the literature.

BACKGROUND: Lymphoproliferative disorder (LPD) has been shown to occur after treatment with methotrexate (MTX). Currently, MTX-LPD has become widely recognized, but its mechanism and prognostic factors remain unclear. CASE PRESENTATION: We report the first case of Epstein-Barr virus (EBV)-associated MTX-LPD of the breast. A 63-year-old Asian woman with long-term rheumatoid arthritis presented to our facility with intermittent fever. A physical examination revealed a 3-cm lump in her left breast. She had been taking MTX for the past 15 years. Laboratory studies revealed slightly elevated levels of EBV-viral capsid antigen antibody immunoglobulin G and EBV nuclear antibody. Contrast-enhanced computer tomography revealed a mass in the left breast, a subcutaneous nodule in the abdomen, a mass in the left lung, and a nodule in the left retroperitoneum. The definitive diagnosis was consistent with MTX-LPD merging into an EBV-positive, diffuse large B-cell lymphoma. Six months following the withdrawal of MTX, the breast mass had markedly shrunk and the patient remained in good health for 1 year with no evidence of relapse of LPD. CONCLUSION: MTX-LPD rarely occurs in the breast, and it is difficult to diagnose because there have only been six reported cases of breast MTX-LPD reported in the literature. EBV-positive MTX-LPD tends to regress spontaneously after MTX withdrawal, and our case also had similar results. It is important to make an appropriate diagnosis of MTX-LPD of the breast based on imaging and pathology to determine the appropriate treatment protocol for this rare disorder.

Study of the protocol used to evaluate skin-flap perfusion in mastectomy based on the characteristics of indocyanine green.

BACKGROUND: Indocyanine green angiography enables real-time visualization of blood vessels at depths of up to 10 mm beneath the body surface, thereby aiding the evaluation of the viability of skin flaps and predicting necrosis in surgical fields requiring good tissue perfusion. Although skin-flap necrosis also occurs in mastectomy without reconstruction, most studies have focused on reconstructive plastic surgery. Several patients undergoing mastectomy are eligible for postoperative adjuvant therapy, but complications can lead to delays in treatment and thus require prevention. However, a lack of a standard protocol for evaluating skin-flap perfusion using indocyanine green necessitates the study of its characteristics to facilitate comparison of the perfusion rate among individuals. METHODS: This retrospective study focused on the characteristics of indocyanine green and established a protocol for indocyanine green angiography using laser-assisted imaging (SPY system) to predict postoperative skin-flap necrosis from intraoperative images of 30 patients who underwent mastectomy without reconstruction. RESULTS: Our protocol predicted postoperative skin-flap necrosis as follows. First, the intravenous dose and concentration were set at 2.5 mg/mL and 0.05 mg/kg, respectively. Second, the timing of measurement was set to 100 s after the entry of indocyanine green into the skin (plateau phase); the analysis pattern was set to single frame. Third, comparisons among individuals were made using relative values. CONCLUSIONS: We analyzed the area of postoperative flap necrosis using this protocol. We found that the intraoperative images showed decreased perfusion in that area, which was useful in predicting skin-flap necrosis, as reported by previous breast reconstruction studies.

Hydronephrosis Caused by Metastatic Breast Cancer.

Breast cancer metastasizes mainly to organs such as bone, lung, and liver, whereas metastases to the peritoneum and urinary tract are rare. Metastasis to the peritoneum or urinary tract may result in renal dysfunction, infection, and painful hydronephrosis. In our hospital, 1,409 breast cancer surgeries were performed between January 2004 and December 2015, and 7 cases of hydronephrosis associated with recurrence were observed. The median age of patients was 69 years (57-79 years). The median time from surgery to diagnosis of hydronephrosis was 47 months (20-70 months). Histology was invasive ductal carcinoma (IDC) in 6 cases and invasive lobular carcinoma (ILC) in 1 case. There were 6 bilateral cases and 1 unilateral case of hydronephrosis. The causes were retroperitoneal metastasis in 5 cases and lymph node metastasis in 2 cases. The hydronephrosis was untreated in 2 cases, and treated with a ureteral stent in 2 cases, nephrostomy in 1 case, and nephrostomy due to ureteral stent failure in 2 cases. The median survival from the onset of hydronephrosis was 12 months (3-57 months). Although the probability of hydronephrosis in breast cancer recurrence was not high, care must be taken to avoid renal dysfunction, infection, or pain, which may require treatment.

[A Case of Ramucirumab-Related Small Intestinal Perforation in Gastric Cancer].

A 54-year-old man underwent laparoscopic distal gastrectomy with D2 lymph node dissection and ante-colic Roux-en-Y reconstruction for gastric cancer. The histopathological diagnosis was pT2N3aM0, pStage ⅢA, HER2 negative. After 8 courses of S-1 plus oxaliplatin as adjuvant chemotherapy, he was diagnosed as peritoneal dissemination and treated with ramucirumab(RAM)plus paclitaxel(PTX). On the 12th day of course 10, he visited to our hospital with abdominal pain. CT showed free air and massive ascites. Emergent surgery was performed under the diagnosis of gastrointestinal perforation. A small intestinal perforation in front of the jejunal limb near gastric-jejunal anastomosis was identified and there was no peritoneal dissemination. We performed partial resection of remnant stomach and jejunal limb by linear stapler and reconstruction by end to side gastric-jejunal anastomosis. Because the gastric and intestinal wall were quite fragile and RAM impaired wound healing as adverse event, we feared about leakage, but he had no major postoperative complications and discharged on the 33th day after surgery. After 24 courses of nivolumab as third-line chemotherapy, the peritoneal dissemination disappeared. He has been alive without recurrence for about 1 year since then.

[A Case of Pneumocystin a Patient with Pneumonia That Developed during Chemotherapy for Sigmoid Cancer].

A 63-year-old man was diagnosed with advanced sigmoid cancer of pT3, pN0, sM1c, sP3, fStage Ⅳ post-operation. After CAPOX plus Bmab as the first-line chemotherapy, he underwent IRIS plus Bmab as the second-line chemotherapy. After 1 course of IRIS plus Bmab, he was admitted to the hospital for fever, dyspnea, and general fatigue. The white blood cell count was 6.2×10 3/mL, and the C-reactive protein was elevated to 12.9 mg/dL. The PaO2 of the artery blood gas analysis in room air was 46.3 mmHg, suggesting respiratory failure. He was diagnosed with PCP based on the bilateral diffused ground-glass opacities on chest CT along with an elevated serum b-D-glucan. The treatment of trimethoprim-sulfamethoxazole and steroid was then initiated. After the patient's clinical condition improved, he was discharged on day 27 post-admission.

Predictors for upstaging of ductal carcinoma in situ (DCIS) to invasive carcinoma in non-mass-type DCIS.

Preoperatively diagnosed ductal carcinoma in situ (DCIS) is sometimes upstaged to invasive cancer by postoperative pathological examination. Various preoperative factors associated with upstaging to invasive cancer have been reported; however, this subject remains to be clarified. DCIS takes various forms on imaging, but many cases show non-mass-type lesions. In non-mass-type DCIS, recognizing the presence of invasion is difficult. To investigate predictors associated with upstaging to invasive cancer more precisely, we examined only non-mass-type DCIS. The present study retrospectively analyzed 101 patients diagnosed with non-mass-type DCIS preoperatively on breast biopsy at our institution between 2007 and 2017. Data were analyzed using Fisher's exact probability test and two-sample t-tests. Multivariate analysis was performed using logistic regression. The results showed that 27 patients (27%) were finally diagnosed with invasive cancer. Univariate analysis revealed abnormal result of palpation on breast examination (P=0.05), comedo necrosis (P=0.05), and HER2 status (P=0.02) as significant predictors. Multivariate analysis revealed an abnormal result of palpation as an independent predictor of invasive cancer underestimation (odds ratio 4.76; confidence interval 1.44-15.7; P=0.01). In conclusion, preoperatively diagnosed non-mass-type DCIS represented an underestimation in approximately 27% of cases. In particular, the presence of a clinically abnormal palpation increases the chance of upstaging to invasive cancer.

Discovery of the novel HLA-B allele, HLA-B*51:01:01:36 in a Japanese individual.

HLA-B*51:01:01:36 differs from HLA-B*51:01:01:01 by one nucleotide difference at position -230(G>T) with no amino acid change.

Time dependence of multi-ion absorption into human enamel from surface prereacted glass-ionomer (S-PRG) filler eluate.

Ion incorporation into the tooth is expected to be effective for caries prevention. Time-dependent ion incorporation released from surface pre-reacted glass-ionomer (S-PRG) filler eluate into tooth enamel was estimated by using inductively coupled plasma atomic emission spectroscopy (ICP-AES). Al, B, and Sr contents in enamel were increased in a time-dependent manner with immersion in S-PRG eluate. Clear ion incorporation was observed after 1 h of immersion in S-PRG filler eluate. Sr showed remarkable incorporation in enamel -up to 7,900 ppm- after 28 days of immersion. Sr and B incorporation rapidly occurred in S-PRG filler eluate, compared with their single component solutions. Simultaneous incorporation of cations and anions from S-PRG eluate occurred under balanced charge and may assist in rapid ion incorporation. Thus, various useful ions could be effectively incorporated into tooth enamel by applying S-PRG filler or its eluate; a bioactive effect can be expected.

[A Case of Nephrotic Syndrome Due to SOX plus Bmab Therapy for Liver Metastasis of Rectal Cancer].

A 66-year-old man was postoperatively diagnosed with pT4a, pN2, cM1a(H2), cP0, fStage Ⅳ, RAS wild type rectal cancer. He underwent SOX plus Bmab chemotherapy 4 weeks later. After 9 courses of SOX plus Bmab, he was admitted to the hospital for leg edema and proteinuria(4+). Because of severe proteinuria(14.7 g/day)and low protein(Alb 2.0 g/dL, TP 4.9 g/dL), he was diagnosed with nephrotic syndrome. His general condition improved on stopping chemotherapy and administration of conservative treatment, and he was discharged on day 20 after admission. The proteinuria improved 3 months later. He had been undergoing SOX chemotherapy for 4 months.

[A Case of Breast Cancer Complicated with Castleman's Disease].

The patient was a 57-year-old woman with Castleman's disease. The follow-up CT scans obtained during the treatment of Castleman's disease, detected a 15mm nodule in the right breast AC area, and the patient was diagnosed with breast cancer. Lymphadenopathy was noted on both sides of the axilla; however, it was considered to be due to Catsleman's disease. Mastectomy and sentinel lymph node biopsy were performed with preoperative diagnosis of cT1cN0M0, cStage Ⅰ. Rapid diagnosis of the sentinel lymph node during the operation showed a metastatic tumor measuring 3mm and axillary dissection was performed. However, no metastasis was found in the dissected lymph node, which was, therefore, considered as an enlargement due to Castleman's disease.

The effects of ipragliflozin on the liver-to-spleen attenuation ratio as assessed by computed tomography and on alanine transaminase levels in Japanese patients with type 2 diabetes mellitus.

We assessed the effects of a 12-week ipragliflozin treatment on the liver-to-spleen attenuation ratio (L/S ratio) using computed tomography and on alanine transaminase (ALT) levels in Japanese patients with type 2 diabetes mellitus (T2DM). Sixty-two patients with T2DM [age, 56 ± 8 years; hemoglobin A1c (HbA1c) levels, 8.1 ± 0.9%; body mass index (BMI), 27.5 ± 3.3 kg/m2] were randomly assigned in a 2:1 ratio to receive ipragliflozin (50 mg/day; ipragliflozin group; n = 40) or continued treatment (control group; n = 22) for 12 weeks. The primary endpoints were changes in ALT levels; the secondary endpoints included changes in the L/S ratio and in the visceral fat area (VFA) and subcutaneous fat area (SFA) before and after 12 weeks of the treatment as assessed by computed tomography. ALT levels (-12.45 vs. +5.82 IU/l, P < 0.001), L/S ratio (+0.07 vs. -0.08, P < 0.001), SFA (-5.8 vs. +13.3 cm2, P < 0.05), and VFA (+1.4 vs. +20.4 cm2, P < 0.05) significantly changed from baseline in the ipragliflozin group compared with the values in the control group. Multiple regression analysis among all subjects revealed that the independent factor contributing to the %ΔALT and %ΔL/C ratio was treatment group alone (ipragliflozin group = 1; control group = 0; ß coefficient = -32.08, P < 0.001 and ß coefficient = 19.98, P < 0.05, respectively). Thus, ipragliflozin may lower ALT levels associated with increased L/S ratios, indicating its potential therapeutic efficacy in T2DM-associated hepatic steatosis.

[A Case of Rapidly Advancing G-CSF Producing Pleomorphic Carcinoma of the Breast Appearing as an Inflammatory Breast Cancer].

We report a rare case of pleomorphic carcinoma of the breast, suspected of being a granulocyte-colony stimulating factor (G-CSF)producing tumor, in a 75-year-old woman. She presented with a red and swollen breast, 3 weeks after undergoing core needle biopsy(CNB). Her leukocyte counts and C-reactive protein(CRP)levels were markedly high. At first, she was suspected to have an abscess and was initiated on a course of antibiotics. However, her condition rapidly deteriorated; therefore, she underwent an emergency mastectomy. Despite undergoing postoperative radiation therapy, 2 months after the operation, multiple metastatic foci were found in the lungs and liver, and she died of the disease 3 months after her first visit. After the operation, her leukocyte count had quickly returned to normal, but it increased as the disease progressed. These findings support the conclusion that this carcinoma was producing G-CSF. The final pathological diagnosis was G-CSF producing pleomorphic carcinoma of the breast.

Periappendicitis during adalimumab treatment for ileocecal Crohn's disease in a 29-year-old male.

A 29-year-old male was diagnosed with ileocolic Crohn's disease (CD) approximately 2 years ago. Adalimumab was prescribed as CD remission induction therapy. Three months after beginning adalimumab, watery diarrhea and lower abdominal pain developed. He was admitted under a diagnosis of CD exacerbation. Despite fasting and antibiotic treatment, symptoms of acute panperitonitis appeared. He was diagnosed as acute appendicitis and we performed emergency surgery for peritoneal drainage and ileocecal resection on the fifth hospital day. We diagnosed periappendicitis based on the operative findings. This is the first report of periappendicitis with CD during adalimumab treatment.

PAPD5-mediated 3' adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease.

Next-generation sequencing experiments have shown that microRNAs (miRNAs) are expressed in many different isoforms (isomiRs), whose biological relevance is often unclear. We found that mature miR-21, the most widely researched miRNA because of its importance in human disease, is produced in two prevalent isomiR forms that differ by 1 nt at their 3' end, and moreover that the 3' end of miR-21 is posttranscriptionally adenylated by the noncanonical poly(A) polymerase PAPD5. PAPD5 knockdown caused an increase in the miR-21 expression level, suggesting that PAPD5-mediated adenylation of miR-21 leads to its degradation. Exoribonuclease knockdown experiments followed by small-RNA sequencing suggested that PARN degrades miR-21 in the 3'-to-5' direction. In accordance with this model, microarray expression profiling demonstrated that PAPD5 knockdown results in a down-regulation of miR-21 target mRNAs. We found that disruption of the miR-21 adenylation and degradation pathway is a general feature in tumors across a wide range of tissues, as evidenced by data from The Cancer Genome Atlas, as well as in the noncancerous proliferative disease psoriasis. We conclude that PAPD5 and PARN mediate degradation of oncogenic miRNA miR-21 through a tailing and trimming process, and that this pathway is disrupted in cancer and other proliferative diseases.

TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions.

Mammalian tribbles homolog 1 (TRIB1) regulates hepatic lipogenesis and is genetically associated with plasma triglyceride (TG) levels and cholesterol, but the molecular mechanisms remain obscure. We explored these mechanisms in mouse livers transfected with a TRIB1 overexpression, a shRNA template or a control (LacZ) adenovirus vector. The overexpression of TRIB1 reduced, whereas induction of the shRNA template increased, plasma glucose, TG, and cholesterol and simultaneously hepatic TG and glycogen levels. The involvement of TRIB1 in hepatic lipid accumulation was supported by the findings of a human SNP association study. A TRIB1 SNP, rs6982502, was identified in an enhancer sequence, modulated enhancer activity in reporter gene assays, and was significantly (P=9.39 × 10(-7)) associated with ultrasonographically diagnosed non-alcoholic fatty liver disease in a population of 5570 individuals. Transcriptome analyses of mouse livers revealed significant modulation of the gene sets involved in glycogenolysis and lipogenesis. Enforced TRIB1 expression abolished CCAAT/enhancer binding protein A (CEBPA), CEBPB, and MLXIPL proteins, whereas knockdown increased the protein level. Levels of TRIB1 expression simultaneously affected MKK4 (MAP2K4), MEK1 (MAP2K1), and ERK1/2 (MAPK1/3) protein levels and the phosphorylation of JNK, but not of ERK1/2. Pull-down and mammalian two-hybrid analyses revealed novel molecular interaction between TRIB1 and a hepatic lipogenic master regulator, MLXIPL. Co-expression of TRIB1 and CEBPA or MLXIPL reduced their protein levels and proteasome inhibitors attenuated the reduction. These data suggested that the modulation of TRIB1 expression affects hepatic lipogenesis and glycogenesis through multiple molecular interactions.