Effect of NIMA-related kinase 2B on the sensitivity of breast cancer to paclitaxel in vitro and vivo.

NIMA-related kinase 2B has been known to be an important centrosome regulatory factor. The aim of this study was to investigate the effect of NIMA-related kinase 2B on the sensitivity of breast cancer to paclitaxel. We detected the expression of NIMA-related kinase 2B messenger RNA in MCF-10 cells, including MCF-10A, MCF-10AT, MCF-10DCIS.com , and MCF-10CA1a. The influence of NIMA-related kinase 2B in nude mouse was also detected. The association between NIMA-related kinase 2B and clinicopathological factors was explored in invasive ductal carcinoma tissues. NIMA-related kinase 2B was lowly expressed in the precancerous cells, MCF-10A and MCF-10AT, and it was highly expressed in carcinomatous cells, MCF-10DCIS.com and MCF-10CA1a. The upregulation of NIMA-related kinase 2B can introduce the growth of MCF-10AT cells, knockdown of NIMA-related kinase 2B could remarkably inhibit cell proliferation in MCF-10DCIS.com and MCF-10 CA1a cells. Comparing the volume of the xenografts in nude mouse, we found that the tumors treated by NIMA-related kinase 2B small interfering RNA associated with paclitaxel were the smallest among all the groups. Expression of NIMA-related kinase 2B messenger RNA was associated with higher histological grades, positive lymph node, and high Ki67 index (>20%). The partial response rates were 75.0% in NIMA-related kinase 2B negative (NIMA-related kinase 2B-) patients and 15.8% in NIMA-related kinase 2B++ patients. The progressive disease rates were 10.0% in NIMA-related kinase 2B- patients and 52.6% in NIMA-related kinase 2B++ patients ( p = 0.002). Our findings suggested that NIMA-related kinase 2B could play a role in the development and progression of breast cancer. Combination treatment using NIMA-related kinase 2B small interfering RNA and paclitaxel might be a novel potential therapy method for breast cancer.

Clinicopathologic characteristics and molecular subtypes of microinvasive carcinoma of the breast.

Patients with microinvasive carcinoma often have favorable prognosis, but it remains unclear whether this special type of breast cancer represents a distinct morphological entity with its own biological features and clinical behavior distinct from those of ductal carcinoma in situ (DCIS). The study is a retrospective analysis of a large patient cohort from a single institution. One hundred and thirty one microinvasive carcinoma and 451 DCIS cases were collected. ER, PR, HER2, and Ki67 were examined by immunohistochemistry in pathological sections. We assessed the clinicopathologic characteristics, molecular features, and survival status of microinvasive carcinoma and compared to those of DCIS. Microinvasive carcinoma differed from DCIS with respect to tumor size, lymph node status, and initial presentation (P < 0.05). There was a significant difference in nuclear grade among microinvasive carcinoma of different molecular subtype (P < 0.05). The clinicalpathologic features and outcomes of patients with microinvasive carcinoma were similar to those with DCIS. The 5-year OS rate for microinvasive carcinoma and DCIS patients was 99.0 and 99.2%, respectively. A combination of pathologic, clinical, and molecular factors may ultimately reveal more powerful and robust measures for disease classification than any one modality alone. Microinvasive carcinoma does not significantly predict for worse DFS or OS in comparison with patients with DCIS.

TrkC expression predicts favorable clinical outcome in invasive ductal carcinoma of breast independent of NT-3 expression.

BACKGROUND: TrkC, a member of neurotrophin receptor family, functions not only as an oncogene, but also act as a tumor suppressor via a manner of dependence receptor in human malignant tumors. Little is known on the action of TrkC for the clinical prognosis and the progression of breast cancer according to the availability of its ligand NT-3. We sought to investigate the prognostic relevance of NT-3-TrkC axis in breast cancer and estimate its role during the process of breast cancer progression. METHODS: 236 cases of invasive ductal carcinoma (IDC), 60 pure ductal carcinoma in situ (DCIS) and 30 normal breast tissue (NBT) between 2004 and 2005 were included in the study. Spearman's rank correlation test was used to analyze the association of NT-3-TrkC expression and breast cancer progression. The Kaplan-Meier method and Cox proportional hazards model were performed to identify the relevant prognostic factors. RESULTS: 50.4% IDC tumors displayed absent or low TrkC expression, while 49.6% was high TrkC expression. TrkC expression was negatively associated with lymph node metastasis (P = 0.029) and tumor proliferation (P = 0.015). Patients with lower TrkC expressing tumors had a higher risk of recurrence (odds ratio, 0.401; 95% confidence interval, 0.207-0.778; P = 0.007). The layered analysis indicated that patients with high TrkC expression tumors had a favor disease-free survival whether NT-3 and TrkC were co-expressed or solitarily expressed in the tumor (P = 0.000). NT-3 was demonstrated to be not a predictor of IDC patients' prognosis. But NT-3 expression was inversely correlated with the progression of breast cancer (r = -0.341, P = 0.000), since more IDC tumors showed high NT-3 expression than DCIS tumors (51.7% vs. 25.9%), while no NBT showed high NT-3 expression, as well. CONCLUSION: The study indicates TrkC expression reduces tumor relapse independent of NT-3 availability in the IDC. Elevated NT-3 expression contributes to the progression of breast cancer.

An associated classification of triple negative breast cancer: the risk of relapse and the response to chemotherapy.

BACKGROUND: Triple negative breast cancer (TNBC) is heterogeneous and considered as an aggressive tumor. This study was to evaluate the associated classification and its correlations with prognosis and the response to chemotherapy in Chinese women. METHODS: Four hundred and twenty-eight cases of invasive TNBC were involved in this study. The expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin 5/6 (CK5/6), Ki67 and p53 were analyzed by immunohistochemistry and compared with patient outcome, and its implications and chemotherapy response were evaluated in four subgroups: typical medullary carcinoma (TMC), atypical medullary carcinoma (AMC), non-specific invasive ductal carcinoma (IDC) and other types. RESULTS: The factors of tumor grade, tumor stage, lymph node status, EGFR/CK5/6 status and p53 labeling index were different among the groups. TMC tumors had the lowest rate of relapse (5.8%), while AMC, IDC and other types were associated with an increased risk of relapse (19.1%, 26.7% and 38.2% respectively). Many factors were risk predictors of relapse for TNBC and IDC, while only positive lymph node was for AMC. For MC tumors, adjunctive chemotherapy decreased the risk of relapse in lymph node positive subgroup (36.8% and 66.7%), while not significant in lymph node negative one (8.1% and 10.0%). CONCLUSION: The classification based on histologic and IHC findings may be a significant improvement in predicting outcome in TNBC. The different chemotherapy response in subgroups may contribute to guiding the treatment of TNBC.

[Expression of vacuole membrane protein 1 and its prognostic value in invasive ductal carcinoma of the breast].

OBJECTIVE: To investigate the expression of vacuole membrane protein 1 (Vmp1) and its prognostic value in invasive ductal carcinoma (IDC) and concomitant ductal carcinoma in situ (DCIS) of the breast. METHODS: The expression and location of Vmp1 in the breast tissues from 102 patients with IDC and 32 concomitant DCIS were detected by immunohistochemical SP method, and the relationship with clinicopathologic parameters was analyzed. RESULTS: Vmp1 expression was observed in the cytoplasm of the cancer cells in 57.8% (59/102) cases, and correlated with grade (χ(2) = 12.644, P = 0.002), pTNM stage (χ(2) = 11.987, P = 0.001), node status (χ(2) = 9.341, P = 0.002), tumor diameter (χ(2) = 7.630, P = 0.022) as well as Nottingham Prognostic Index (NPI;χ(2) = 15.561, P = 0.000). The expression of Vmp1 in concomitant DCIS was higher than that in IDC (81.3% vs 56.3%; χ(2) = 4.655, P = 0.031). In this cohort, the mean disease-free survival was 81.2 months; the 5-year overall survival rate was 90.2% (92/102) and the disease-free survival rate was 81.4% (83/102). Vmp1 expression had significant influence on disease-free survival time, with Vmp1-negative patients showing poor prognosis (χ(2) = 11.192, P = 0.001). COX's proportional hazards regression model revealed that Vmp1 was a protective factor, with relative risk < 1. CONCLUSIONS: The detection of Vmp1 in IDC may be helpful for prognosis prediction; the patients with Vmp1 expression may have a better prognosis.

Invasive cribriform carcinoma in a Chinese population: comparison with low-grade invasive ductal carcinoma-not otherwise specified.

Invasive cribriform carcinoma (ICC) and low-grade invasive ductal carcinoma (IDC) were recently considered to belong to a low-grade breast neoplasia family. However, none of publications has compared ICC and low-grade IDC at present. Meanwhile, in order to evaluate prognostic significance of clinicopathological characteristics of different cribriform contents in ICC and invasive breast cancer with less cribriform structures, a retrospective review of fifty-one cases of ICC and forty cases of invasive breast cancer with less cribriform pattern (less than fifty percent) was conducted in a Chinese population. Forty-nine cases of low-grade IDC without cribriform elements were selected as a control. ICC presented more favorable prognostic factors than those of invasive breast carcinoma with less cribriform pattern and low-grade IDC, such as smaller tumor size, less frequent axillary lymph node involvement, higher positive rate of estrogen receptor and/or progestogen receptor expression, and lower proliferation index. The expression of human epidermal growth factor receptor two in ICC and invasive breast cancer with less cribriform pattern was mostly negative. Pure ICC showed less frequency of axillary lymph node involvement, but not its number. The proliferation index in the pure type was lower, although the tumor size in these two types was not obviously different. Tumors contained cribriform structures had a more favorable prognosis than those with low-grade IDC. Considering the tumor biology, and the benign course of pure ICC studied, chemotherapy may not be indicated in the typical case.

A pure invasive cribriform carcinoma of the breast with bone metastasis if untreated for thirteen years: a case report and literature review.

We report a case of pure invasive cribriform carcinoma of the breast, which had been untreated for thirteen years, being found with bone metastasis at initial presentation, because distant metastasis is rarely found in this tumor. A fifty-nine-year-old postmenopausal woman presented with a large left breast mass. Although she had noticed a lump in a left breast thirteen years ago, she had not sought treatment. The tumor had enlarged gradually since from one year before and become ulcerated. The two enlarged axillary lymph nodes were also palpable. After two cycles of neoadjuvant chemotherapy, she underwent left radial mastectomy with a free skin graft. Emission computed tomography result has confirmed bone metastasis. The histological diagnosis of the tumor revealed the pure invasive cribriform carcinoma, since over than ninety percent of invasive tumor components showed a characteristic cribriform growth, and the remainder was tubular carcinoma. She has been well without evidence of tumor recurrence for seven years after surgery and several routine postoperative therapies. Although with favorable prognosis, pure invasive cribriform carcinoma is still possible to develop into the advanced (Stage four) breast cancer if untreated for a long time. However, the survival of this patient for free disease after several locoregional and systemic therapies maybe provide a supplement for invasive cribriform carcinoma's excellent prognosis.

Clinicopathologic characteristics and prognosis for molecular subtypes in low-grade breast carcinoma: comparison with grade one invasive ductal carcinoma-not otherwise specified.

The aim of this study was to investigate the clinicopathologic characteristics and prognosis value for molecular subtypes of low-grade breast carcinoma (LGBC) compared with grade one invasive ductal carcinoma-not otherwise specified (G1-IDC-NOS). A retrospective review of 688 LGBC and 1 037 G1-IDC-NOS patients was classified into four different molecular subtypes based on the IHC-based definitions for ER, PR, and c-erbB-2. In LGBC, lymph node metastasis, the percentage of III/IV TNM stages, the expression of Ki-67 and p53 in luminal A subtype were lower than in other subtypes (P<0.01). In addition, the variations of Ki-67 and p53 expression were observed in different subtypes of G1-IDC-NOS (P<0.01). Compared with G1-IDC-NOS, LGBC has higher proportion in the ER positive, PR positive, HER-2 negative, luminal A subtype, Ki-67 negative, and lymph nodes negative group (P<0.01). Furthermore, the overall survival of luminal A and luminal B is higher than triple-negative and HER-2/neu subtype both in LGBC and G1-IDC-NOS in 262 LGBC and 330 G1-IDC-NOS patients with proper follow-up. The classification of molecular subtype together with clinicopathologic factors can significantly improve the traditional prognosticators in predicting outcome for LGBC and G1-IDC-NOS. And it may contribute to guide the treatment for LGBC and G1-IDC-NOS in the future.

Nek2A contributes to tumorigenic growth and possibly functions as potential therapeutic target for human breast cancer.

Nek2A (NIMA-related kinases 2A) has been known as an important centrosome regulatory factor. The aim of this study was to investigate the expression of Nek2A and the role it played in different stages of breast cancer. We detected the expression of Nek2A in both mRNA and protein levels in MCF10 cell lines including MCF-10A, MCF-10DCIS.com, MCF-10CA1a and in human breast samples which contained normal breast tissue (NBT), breast ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC). Our study revealed that the mRNA and protein expression of Nek2A were significantly up-regulated in MCF-10DCIS.com and MCF-10CA1a cell lines as well as in human primary breast cancer tissue (DCIS and IDC). Our study also presented a correlation between Nek2A mRNA expression and some clinic pathological factors. We found that Nek2A mRNA expression was associated with molecular subtypes, ER, PR and Ki-67 immunoreactivity (P<0.05) in DCIS and associated with histological grade, lymph node metastasis, molecular subtypes, c-erbB-2, and Ki-67 expression (P<0.05) in IDC. In addition, we observed that ectopic expression of Nek2A in "normal" immortalized MCF-10A breast epithelial cell resulted in increased Nek2A which lead to abnormal centrosomes. Furthermore, knockdown of Nek2A in MCF-10DCIS.com could remarkably inhibit cell proliferation and induce cell cycle arrest in MCF-10DCIS.com cell line. These data suggested that Nek2A might bear a close relationship with development and progression of breast carcinoma, and highlighted its role as a novel potential biomarker for diagnosis and a possible therapeutic target for human breast cancer especially for DCIS.