Su Hwan Kang

Fibronectin expression in carcinoma cells correlates with tumor aggressiveness and poor clinical outcome in patients with invasive breast cancer

Fibronectin (FN), a large heterodimeric glycoprotein, can be found in soluble form in plasma or in insoluble form as an extracellular matrix protein. Cellular FN is produced by various types of benign and malignant epithelial and mesenchymal cells and is widely distributed in malignant tumors. We evaluated FN expression in cancer cells (epithelial FN; E-FN) and intratumor stroma (stromal FN, S-FN) of 1596 invasive breast cancer samples using immunohistochemistry on tissue microarrays. Correlations of FN expression with clinicopathologic factors and patient survival were investigated. Among 1512 informative cases, E-FN expression was observed in 355 (23.5%) cases, and S-FN expression showed no/weak staining in 362 (23.9%), moderate staining in 744 (49.2%), and strong staining in 406 (26.9%) cases. E-FN expression was correlated with advanced pT (P < .001) and pN (P < .001), histologic type (P = .006), high histologic grade (P < .001), lymphovascular invasion (P < .001), hormone receptor negativity (P < .001), and human epidermal growth factor receptor-2 (HER2) positivity (P < .001). Strong S-FN expression showed an association with advanced pN (P = .002), histologic type (P < .001), high histologic grade (P < .001), lymphovascular invasion (P < .001), and HER2 positivity (P < .001). Patients with E-FN expression showed worse overall survival (P < .001) and disease-free survival (P < .001) than did those with negative expression of FN. E-FN expression was an independent prognostic factor, especially in the hormone receptor-positive group. Expression of S-FN did not have a significant effect on patient survival. In conclusion, E-FN expression could be a promising prognostic marker in patients with invasive breast cancer.

The Efficacy of Arm Node Preserving Surgery Using Axillary Reverse Mapping for Preventing Lymphedema in Patients with Breast Cancer

Purpose The axillary reverse mapping (ARM) technique to identify and preserve arm nodes during sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) was developed to prevent lymphedema. The purpose of this study was to investigate the location and metastatic rate of the arm node, and to evaluate the short term incidence of lymphedema after arm node preserving surgery. Methods From January 2009 to October 2010, 97 breast cancer patients who underwent ARM were included. Blue-dye (2.5 mL) was injected into the ipsilateral upper-inner arm. At least 20 minutes after injection, SLNB or ALND was performed and blue-stained arm nodes and/or lymphatics were identified. Patients were divided into two groups, an arm node preserved group (70 patients had ALND, 10 patients had SLNB) and an unpreserved group (13 patients had ALND, 4 patients had SLNB). The difference in arm circumference between preoperative and postoperative time points was checked in both groups. Results The mean number of identified blue stained arm nodes was 1.4±0.6. In the majority of patients (92%), arm nodes were located between the lower level of the axillary vein and just below the second intercostobrachial nerve. In the arm node unpreserved group, 2 patients had metastasis in their arm node. Among ALND patients, in the arm node preserved group, the difference in arm circumference between preoperative and postoperative time points in ipsilateral and contralateral arms was 0.27 cm and 0.07 cm, respectively, whereas it was 0.47 cm and -0.03 cm in the unpreserved group; one case of lymphedema was found after 6 months. No difference was found between arm node preserved and unpreserved group among SLNB patients. Conclusion Arm node preserving was possible in all breast cancer patients with identifiable arm nodes, during ALND or SLNB, except for those with high surgical N stage, and lymphedema did not develop in patients with arm node preserving surgery.

Neuroendocrine differentiation correlates with hormone receptor expression and decreased survival in patients with invasive breast carcinoma.

Invasive breast carcinoma (IBC) with neuroendocrine (NE) differentiation has been controversial in terms of its definition and clinical outcome. We investigated the incidence and clinical significance of NE differentiation in patients with IBC.

RGS2 Suppresses Breast Cancer Cell Growth via a MCPIP1‐Dependent Pathway

Regulator of G protein signaling 2 (RGS2) is a member of a family of proteins that functions as a GTPase‐activating protein (GAP) for Gα subunits. RGS2 mRNA expression is lower in breast cancerous tissues than in normal tissues. In addition, expression of RGS2 is also lower in MCF7 (cancerous breast cells) than in MCF10A (normal breast cells). Here we investigated whether RGS2 inhibits growth of breast cancer cells. RGS2 overexpression in MCF7 cells inhibited epidermal growth factor‐ or serum‐induced proliferation. In HEK293T cells expressing RGS2, cell growth was also significantly suppressed (In addition, exogenous expression of RGS2 in HEK293T cells resulted in the significant suppression of cell growth). These results suggest that RGS2 may have a tumor suppressor function. MG‐132 treatment of MCF7 cells increased endogenous or exogenous RGS2 levels, suggesting a post‐transcriptional regulatory mechanism that controls RGS2 protein levels. RGS2 protein was degraded polyubiquitinated the K71 residue, but stabilized by deubiquitinase monocyte chemotactic protein‐induced protein 1 (MCPIP1), and not affected by dominant negative mutant (C157A) of MCPIP1. Gene expression profiling study showed that overexpression of RGS2 decreased levels of testis specific Y encoded like protein 5 (TSPYL5), which plays a causal role in breast oncogenesis. TSPYL5 protein expression was low in MCF10A and high in MCF7 cells, showing the opposite aspect to RGS2 expression. Additionally, RGS2 or MCPIP1 overexpression in MCF7 cells decreased TSPYL5 protein level, indicating that RGS2 stabilized by MCPIP1 have diminished TSPYL5 protein levels, thereby exerting an inhibitory effect of breast cancer cell growth. J. Cell. Biochem. 116: 260–267, 2015.

Epithelial-Mesenchymal Transition Phenotype Is Associated with Clinicopathological Factors That Indicate Aggressive Biological Behavior and Poor Clinical Outcomes in Invasive Breast Cancer

Purpose Cancer tissue may display a wide spectrum of expression phenotypes of epithelial-mesenchymal transition (EMT)-related proteins. The purpose of this study was to investigate the clinical significance of EMT phenotypes in breast cancer. Methods We evaluated the expression pattern of the EMT-related proteins E-cadherin and fibronectin in samples from 1,495 patients with invasive breast carcinoma (IBC) on tissue microarrays using immunohistochemistry to investigate the clinical significance of EMT phenotypes in IBC. EMT phenotypes were divided into complete type (E-cadherin-negative/fibronectin-positive), incomplete type (hybrid type, E-cadherinpositive/fibronectin-positive; null type, E-cadherin-negative/fibronectin-negative), and wild-type (E-cadherin-positive/fibronectin-negative). We analyzed the correlation of EMT phenotype with clinicopathological factors and patient survival. Results Loss of E-cadherin was observed in 302 patients (20.2%), and fibronectin was expressed in the cancer cells of 354 patients (23.7%). In total, 64 (4.3%), 290 (19.4%), 238 (15.9%), and 903 (60.4%) samples were categorized as complete, hybrid, null, and wild-type, respectively. The complete EMT phenotype exhibited significant associations with young age (p=0.017), advanced pT (p<0.001) and pN (p<0.001) stages, higher histological grade (p<0.001), lymphovascular invasion (p<0.001), and triple negativity (p<0.001). Patients with complete and hybrid EMT phenotypes had poorer overall survival (OS) and disease-free survival (DFS) than those with the wild-type phenotype (OS, p=0.001; DFS, p<0.001). In multivariate analysis, the hybrid EMT phenotype was an independent prognostic factor for DFS in patients with IBC (p=0.032). Conclusion EMT phenotypes exhibited significant associations with clinicopathological factors indicating aggressive biologic behavior and poor outcome in patients with IBC.

Multiplication of Chromosome 17 Centromere Is Associated with Prognosis in Patients with Invasive Breast Cancers Exhibiting Normal HER2 and TOP2A Status

Purpose This study aimed to investigate the clinical significance of chromosome 17 centromere (CEP17) multiplication (increased copy number of CEP17) related to human epidermal growth factor receptor 2 (HER2) and topoisomerase II alpha (TOP2A) status in patients with invasive breast cancer. Methods We constructed tissue microarrays using 594 invasive breast cancer samples and performed single-color silver-enhanced in situ hybridization (SISH) assay for HER2, TOP2A, and CEP17 to assess for copy number aberrations. The association of CEP17 multiplication with patient survival was analyzed according to HER2 and TOP2A status. Results Among 567 informative cases, HER2 amplification was noted in 22.8%, TOP2A amplification in 8.3% and TOP2A deletion in 11.1%. CEP17 multiplication was identified in 33.2% and was significantly associated with worse overall survival (OS) (p=0.02) and disease-free survival (DFS) (p=0.02). CEP17 multiplication correlated with patient survival in patients with normal TOP2A or non-amplified HER2 status, but the prognostic significance was lost in those with altered TOP2A or amplified HER2. On multivariate analyses, CEP17 multiplication was an independent prognostic factor for poorer OS (p=0.02) and DFS (p=0.01) in patients with normal TOP2A and non-amplified HER2. Conclusion CEP17 multiplication was identified as a promising prognostic marker in patients with invasive breast cancer exhibiting either non-amplified HER2 or normal TOP2A status.

Combined treatment with ABT-737 and VX-680 induces apoptosis in Bcl-2- and c-FLIP-overexpressing breast carcinoma cells

ABT-737, a BH3-mimetic small-molecule inhibitor, binds with very high affinity to Bcl-2, Bcl-xL and Bcl-w, and inhibits their activity. Aurora kinase is one of the serine/threonine kinase family members and is a vital and critical regulator of mitosis and meiosis. In the present study, we investigated the effects and mechanisms of a combined treatment of ABT-737 and VX-680 (Aurora kinase inhibitor) in human breast cancer MDA-MB‑435S cells. ABT-737 plus VX-680 induced caspase-dependent apoptosis in the human breast cancer cells. Combined treatment with ABT-737 and VX-680 led to the downregulation of Bcl-2 expression at the transcriptional level and the downregulation of c-FLIP and Mcl-1 expression at the post-transcriptional level. Overexpression of Bcl-2 or c-FLIP could not block the induction of apoptosis caused by the combined treatment with ABT-737 and VX-680. However, overexpression of Mcl-1 partially inhibited the induction of apoptosis. In contrast, the combined treatment with ABT-737 and VX680 had no effect on the apoptosis in normal cells. Taken together, our study demonstrated that combined treatment with ABT-737 and VX-680 induced apoptosis in anti‑apoptotic protein (Bcl-2 or c-FLIP)-overexpressing cells.

Solitary small bowel metastasis from breast cancer.

The common sites of metastasis of breast cancer are bone, lung, and liver, but gastrointestinal metastasis from breast cancer is rare. We experienced a case of solitary ileal metastasis from breast cancer. A 45-years-old woman presented with melena for several weeks. She showed no other abdominal symptoms. Colonoscopy findings showed an ulcerative mucosal lesion in the terminal ileum, and biopsy was performed. Pathologic examination revealed metastatic carcinoma, originated from breast. The tumor cells were positive for estrogen receptor and negative for Cdx-2. She had had a previous medical history of bilateral breast cancer and undergone breast conserving surgery with sentinel lymph node biopsy for both breasts. The torso positron emission tomography scan at 19 months after surgery showed mildly increased uptake in the terminal ileum which was considered as inflammation. Finally, she was diagnosed with solitary ileal metastasis from breast cancer at 22 months after surgery.

Prognostic significance of CD9 expression differs between tumour cells and stromal immune cells, and depends on the molecular subtype of the invasive breast carcinoma

CD9, a tetraspanin transmembrane protein, modulates cell motility, migration, and proliferation. The aim of this study was to investigate the prognostic significance of CD9 expression in patients with invasive breast carcinoma (IBC).

Immediate Direct-To-Implant Breast Reconstruction Using Anatomical Implants

Background In 2012, a new anatomic breast implant of form-stable silicone gel was introduced onto the Korean market. The intended use of this implant is in the area of aesthetic breast surgery, and many reports are promising. Thus far, however, there have been no reports on the use of this implant for breast reconstruction in Korea. We used this breast implant in breast reconstruction surgery and report our early experience. Methods From November 2012 to April 2013, the Natrelle Style 410 form-stable anatomically shaped cohesive silicone gel-filled breast implant was used in 31 breasts of 30 patients for implant breast reconstruction with an acellular dermal matrix. Patients were treated with skin-sparing mastectomies followed by immediate breast reconstruction. Results The mean breast resection volume was 240 mL (range, 83-540 mL). The mean size of the breast implants was 217 mL (range, 125-395 mL). Breast shape outcomes were considered acceptable. Infection and skin thinning occurred in one patient each, and hematoma and seroma did not occur. Three cases of wound dehiscence occurred, one requiring surgical intervention, while the others healed with conservative treatment in one month. Rippling did not occur. So far, complications such as capsular contracture and malrotation of breast implant have not yet arisen. Conclusions By using anatomic breast implants in breast reconstruction, we achieved satisfactory results with aesthetics better than those obtained with round breast implants. Therefore, we concluded that the anatomical implant is suitable for breast reconstruction.