Sangmin Kim

The prognoses of metaplastic breast cancer patients compared to those of triple-negative breast cancer patients

Metaplastic breast carcinoma (MBC) is a rare, heterogeneous breast cancer characterized by admixture of adenocarcinoma with metaplastic elements, low hormone receptor expression, and poor outcomes. The authors retrospectively reviewed the medical records of 47 MBC patients and 1,346 invasive ductal carcinoma (IDC) patients. Two hundred eighteen of the IDC patients were triple-negative (TN-IDC) for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 (ER-/PR-/HER2-). Patients were surgically treated at the Samsung Medical Center between 2005 and 2009. The MBC patients presented with a larger tumor size, lower lymph node involvement, higher histological and nuclear grades, higher triple negativity (ER-/PR-/HER2-) and higher p53, CK5/6, and EGFR expressions compared with those of the IDC group. However, there were no significant differences in clinicopathological characteristics between MBC and TN-IDC. During the follow-up period (median duration of 30.3xa0months, range 2.6–56.3xa0months), seven (14.9%) MBC patients, and 98 (7.1%) IDC patients had disease recurrence. The three-year disease-free survival (DFS) rate was 78.1% in the MBC group and 91.1% in IDC group (Pxa0<xa00.001). The three-year DFS rate was not significantly different between the MBC and TN-IDC groups (78.1 vs. 84.9%, Pxa0=xa00.114). However, in patients with lymph node metastasis who underwent adjuvant chemotherapy, the three-year DFS rate was 44.4% in the MBC group and 72.5% in the TN-IDC group (Pxa0=xa00.025). The authors found that MBC had a poorer clinical outcome than did IDC. In breast cancer patients with nodal metastasis, MBC had a poorer prognosis than did TN-IDC, despite adjuvant chemotherapy.

Single-cell RNA-seq enables comprehensive tumour and immune cell profiling in primary breast cancer

Single-cell transcriptome profiling of tumour tissue isolates allows the characterization of heterogeneous tumour cells along with neighbouring stromal and immune cells. Here we adopt this powerful approach to breast cancer and analyse 515 cells from 11 patients. Inferred copy number variations from the single-cell RNA-seq data separate carcinoma cells from non-cancer cells. At a single-cell resolution, carcinoma cells display common signatures within the tumour as well as intratumoral heterogeneity regarding breast cancer subtype and crucial cancer-related pathways. Most of the non-cancer cells are immune cells, with three distinct clusters of T lymphocytes, B lymphocytes and macrophages. T lymphocytes and macrophages both display immunosuppressive characteristics: T cells with a regulatory or an exhausted phenotype and macrophages with an M2 phenotype. These results illustrate that the breast cancer transcriptome has a wide range of intratumoral heterogeneity, which is shaped by the tumour cells and immune cells in the surrounding microenvironment.

Berberine inhibits growth of the breast cancer cell lines MCF-7 and MDA-MB-231.

The effects of berberine on the behavior of breast tumors have not yet been established. To determine whether this compound is useful in the treatment of breast cancer, we analyzed the impact of berberine on the human breast cancer cell lines MCF-7 and MDA-MB-231 cells. Berberine was added to proliferating MCF-7 and MDA-MB-231 cells in culture. Following treatment, changes in cell growth characteristics such as proliferation, cell cycle duration, and the degree of apoptosis were assayed. Following berberine treatment, a time-dependent reduction in proliferation was observed in both cell lines at differing concentrations: 20 microM for MCF-7 and 10 microM for MDA-MB-231 cells. Annexin V staining showed an increase in apoptosis in both cell lines of 31 % in MCF-7 and 12 % in MDA-MB-231 cells compared to their respective controls. In addition, 12 % of the MCF-7 cells were arrested at G0/G1, compared to 62 % of control cells. These results demonstrate that treatment with berberine inhibits growth in both MDA-MB-231 and MCF-7 cells. In addition, they show that this partly occurs through the induction of apoptosis in MDA-MB-231 cells, and through both cell cycle arrest and induction of apoptosis in MCF-7 cells. Thus, berberine may be a novel therapeutic drug for breast cancer.

Silibinin suppresses TNF-α-induced MMP-9 expression in gastric cancer cells through inhibition of the MAPK pathway.

Tumor necrosis factor (TNF)-α is one of the pro-inflammatory cytokines highly expressed in Helicobacter pylori that inhibits gastric acid secretion. In this study we determined the effect of silibinin on TNF-α-induced MMP-9 expression in gastric cancer cell lines. MMP-9 mRNA and protein expression was dose-dependently increased by TNF-α in SNU216 and SNU668 gastric cancer cells. On the other hand, TNF-α-induced MMP-9 expression was dose-dependently suppressed by silibinin. To verify the regulatory mechanism of silibinin on TNF-α-induced MMP-9 expression, the gastric cancer cell lines were pretreated with silibinin prior to TNF-α. TNF-α-induced MMP-9 expression was inhibited by the MEK1/2 specific inhibitor, UO126. Finally, we investigated the effect of adenoviral constitutively active (CA)-MEK and CA-Akt on MMP-9 expression. The expression of MMP-9 was significantly increased by CA-MEK overexpression, but not by CA-Akt overexpression. Taken together, we suggest that silibinin down-regulates TNF-α-induced MMP-9 expression through inhibition of the MEK/ERK pathway in gastric cancer cells.

Does pre-operative breast magnetic resonance imaging in addition to mammography and breast ultrasonography change the operative management of breast carcinoma?

Magnetic resonance imaging (MRI) has been used for the local staging of breast cancer, especially to determine the extent of multiple lesions and to identify occult malignancies. The aim of this study was to evaluate the effect of pre-operative MRI on the surgical treatment of breast cancer. Between January 2006 and May 2007, 535 newly diagnosed breast cancer patients who planned to undergo breast conserving surgery had clinical examinations, bilateral mammography, breast ultrasonography, and breast MRI. The radiologic findings and clinicopathologic data were reviewed retrospectively. Ninety-eight (18.3%) patients had additional lesions, shown as suspicious lesions on breast MRI, but not detected with conventional methods. Eighty-four (15.7%) of these patients had a change in surgical treatment plans based on the MRI results. Forty-seven (8.8%) of the 84 patients had additional malignancies; the other 37 patients (6.9%) had benign lesions. The positive predictive value for MRI-based surgery was 56.0% (47 of 84 patients). During the period of study, the use of pre-operative MRI was increased with time (OR 1.20; 95% CI 1.16–1.23; Pxa0<xa00.001), but the mastectomy rate did not change significantly (OR 0.98; 95% CI 0.95–1.00; Pxa0=xa00.059). Multiple factors were analyzed to identify the patients more likely to undergo appropriate and complete surgery based on the additional findings of the pre-operative MRI, but the results were not statistically significant. This research suggests that a pre-operative MRI can potentially lower the rate of incompletely excised malignancies by identifying additional occult cancer prior to surgery and does not lead to an increase in the mastectomy rate; however, because some benign lesions are indistinguishable from suspicious or malignant lesions, excessive surgical procedures are unnecessarily performed in a significant portion of patients. In the future, the criteria for the use of MRI in local staging of breast cancer should be established.

Comparison between screen-detected and symptomatic breast cancers according to molecular subtypes

Breast cancer screening programs make it possible to detect early cancer, thus reducing breast cancer mortality. We studied the clinicopathologic characteristics and prognosis of screen-detected invasive breast cancer compared with symptomatic breast cancer. And we compared the result according to molecular subtypes (luminal A, luminal B, Her2, and triple negative), with the goal of identifying the role of screening in each subtypes. From January 2002 to June 2008, 3,141 patients who underwent surgery for the treatment of invasive ductal carcinoma at Samsung Medical Center were included. Among them, 1,025 patients were screen-detected, and 2,116 patients who were screened over 2xa0years or never were symptomatic. We retrospectively reviewed the clinical and pathologic data. Screen-detected breast cancer was associated with older age, smaller tumor size, more hormone-receptor positive, less lymph node involvement, earlier stage, and reduced mortality compared with symptomatic breast cancer (Pxa0<xa00.001). According to the molecular subtype, luminal A was most common (63.6%) and showed the most obvious survival benefit in screen-detected tumors in comparison with symptomatic tumors (5-year OS: 99.7 vs. 96.5%, 5-year DFS: 96.4 vs. 90.7%). Screen detection was independently associated with improved overall and disease-free survival outcomes after adjustment for covariates (HR 0.32, Pxa0=xa00.035; HR 0.58, Pxa0=xa00.020, respectively) only in the luminal A subtype. Differences in pathological features such as tumor size, nodal status, grade, and age at diagnosis with different molecular subtype distributions may explain the survival advantage of patients with screen-detected breast cancer. Screening programs seem to have a different efficacy depending on the molecular subtype of the breast cancer, especially in the luminal A subtype, for which screen detection acts as an independent prognostic factor itself.

Berberine Suppresses TPA-Induced Fibronectin Expression through the Inhibition of VEGF Secretion in Breast Cancer Cells

Background/Aims: Berberine (BBR) is an isoquinoline alkaloid and is beneficial for the anticancer effect on a variety of human tumor cells. However, BBRs anti-angiogenesis property and its clinical potential as an inhibitor of tumor angiogenesis in breast cancer cells have not been fully elucidated. Here, we investigated the effect of BBR on TPA-induced VEGF and fibronectin (FN) as well as VEGF-induced FN in breast cancer cells. Methods: The secretion of VEGF protein was detected by ELISA. Fibronectin mRNA and protein expression was analyzed by Real-Time PCR and western blotting, respectively. The overexpressions of CA-MEK, and CA-Akt were examined by adenovirus system. Results: Our results showed that TPA, a tumor promoter, significantly increased the level of VEGF and FN expression in both MCF7 and T47D breast cancer cells. On the other hand, TPA-induced VEGF and FN expression was suppressed by LY294002, a PI-3K inhibitor. In contrast, the level of FN expression also significantly increased by constitutively active (CA)-AKT overexpression. We also found that TPA-induced VEGF and FN expression was decreased by BBR treatment. Finally, our results showed that VEGF augmented the expression of FN whereas VEGF-induced FN expression was decreased by BBR treatment. Conclusion: Taken together, we suggest that BBR may suppress TPA-induced VEGF and FN as well as VEGF-induced FN through the inhibition of the PI-3K/AKT pathway in breast cancer cells. Therefore, we suggest that BBR may be used as a candidate drug for the inhibition of angiogenesis of human breast cancer.

TPA-induced p21 expression augments G2/M arrest through a p53-independent mechanism in human breast cancer cells

The tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), has a differential role on the regulation of the cell cycle in a variety of tumor cells. The mechanism between TPA and the cell cycle in breast cancer is not fully understood. Therefore, we investigated the regulatory mechanism of TPA on control of the cell cycle of breast cancer cells. Our results showed that TPA increased the level of p21 expression in MCF-7 cells with wild-type p53 and MDA-MB-231 cells with mutant p53 in a dose-dependent manner. In contrast, TPA decreased the expression of p53 in MCF-7 cells, but did not affect MDA-MB-231 cells. We next examined the regulatory mechanism of TPA on p21 and p53 expression. Our results showed that the TPA-induced up-regulation of p21 and down-regulation of p53 was reversed by UO126 (a MEK1/2 inhibitor), but not by SP600125 (a JNK inhibitor) or SB203580 (a p38 inhibitor), although TPA increased the phosphorylation of ERK and JNK in MCF-7 cells. In addition, the TPA-induced arrest of the G2/M phase was also recovered by UO126 treatment. To confirm the expression of p21 through the MEK/ERK pathway, cells were transfected with constitutively active (CA)-MEK adenovirus. Our results showed that the expression of p21 was significantly increased by CA-MEK overexpression. Taken together, we suggest that TPA reciprocally regulates the level of p21 and p53 expression via a MEK/ERK-dependent pathway. The up-regulation of p21 in response to TPA is mediated through a p53-independent mechanism in breast cancer cells.

A functional comparison between the HER2(high)/HER3 and the HER2(low)/HER3 dimers on heregulin-β1-induced MMP-1 and MMP-9 expression in breast cancer cells.

Overexpression of HER2 correlates with more aggressive tumors and increased resistance to cancer chemotherapy. However, a functional comparison between the HER2high/HER3 and the HER2low/HER3 dimers on tumor metastasis has not been conducted. Herein we examined the regulation mechanism of heregulin-β1 (HRG)-induced MMP-1 and -9 expression in breast cancer cell lines. Our results showed that the basal levels of MMP-1 and -9 mRNA and protein expression were increased by HRG treatment. In addition, HRG-induced MMP-1 and -9 expression was significantly decreased by MEK1/2 inhibitor, U0126 but not by phosphatidylinositol 3-kinase (PI-3K) inhibitor, LY294002. To confirm the role of MEK/ERK pathway on HRG-induced MMP-1 and -9 expression, MCF7 cells were transfected with constitutively active adenoviral-MEK (CA-MEK). The level of MMP-1 and -9 expressions was increased by CA-MEK. MMP-1 and -9 mRNA and protein expressions in response to HRG were higher in HER2 overexpressed cells than in vector alone. The phosphorylation of HER2, HER3, ERK, Akt, and JNK were also significantly increased in HER2 overexpressed MCF7 cells compared with vector alone. HRG-induced MMP-1 and -9 expressions were significantly decreased by lapatinib, which inhibits HER1 and HER2 activity, in both vector alone and HER2 overexpressed MCF7 cells. Finally, HRG-induced MMP-1 and MMP-9 expression was decreased by HER3 siRNA overexpression. Taken together, we suggested that HRG-induced MMP-1 and MMP-9 expression is mediated through HER3 dependent pathway and highly expressed HER2 may be associated with more aggressive metastasis than the low expressed HER2 in breast cancer cells.

A new subfascial approach in open thyroidectomy: efficacy for postoperative voice, sensory, and swallowing symptoms. A randomized controlled study.

AbstractBackgroundAfter open thyroidectomy, patients usually complain of voice, sensory, and swallowing symptoms. We approached the thyroid via the subfascial method to reduce these symptoms and compared postthyroidectomy symptoms with the conventional subplatysmal method.nMethodsEighty-six patients undergoing thyroidectomy were recruited and randomized into either a conventional subplatysmal approach group (subplatysmal, 42 patients) group or a subanterior fascia of strap muscle approach group (subfascial, 44 patients). Voice symptoms were assessed using the Voice Handicap Index questionnaire and acoustic voice analysis. Sensory alterations were evaluated by the light touch and pain touch methods. Swallowing symptoms were assessed using the Swallowing Impairment Score (SIS) questionnaire, barium swallowing time, and hyoid bone movement range. Each variable was measured preoperatively, and at 2xa0weeks and 3xa0months after thyroidectomy.nResultsIn both groups, the subjective symptoms of voice, sensation, and swallowing were significantly worsened at 2xa0weeks after operation, but improved 3xa0months after operation. Patients in the subplatysmal group had worse SIS scores than patients in the subfascial group (pxa0=xa00.016) and delayed barium swallowing time 2xa0weeks after operation (pxa0=xa00.008 compared to preoperative level). In the cohort over 50xa0years of age, SIS score did not recover to preoperative levels in the subplatysmal group 3xa0months after operation (pxa0=xa00.005 compared to preoperative level).ConclusionsThe subfascial approach may be an effective method for reducing postthyroidectomy swallowing symptoms based on swallowing impairment score, especially in patients over 50xa0years of age.