Biomedical subjects

Zhen-Zhou Shen

Publications and source records attributed to Zhen-Zhou Shen.

16 recordsLinked to original sources

PubMed2006

Gene expression profile analysis of an isogenic tumour metastasis model reveals a functional role for oncogene AF1Q in breast cancer metastasis.

To study the molecular mechanisms underlying breast cancer metastasis, gene expression profile analysis was performed on two well-established breast cancer cell lines with high and low metastatic potentials: MDA-MB-435HM and MDA-MB-435LM. The analysis was conducted using cDNA microarrays containing 8000 genes. Of 60 differentially expressed genes, ALL1-fused gene from chromosome 1q (AF1Q), a putative oncogene not described previously in breast cancer, was identified and found to be over-expressed in MDA-MB-435HM cells compared with MDA-MB-435LM cells. The results indicate that AF1Q may play an important role in breast cancer metastasis. To test this hypothesis, we generated an AF1Q high-expression cell line by stable transfection of AF1Q cDNA into MDA-MB-435LM cells. Results showed that over-expression of AF1Q led to a marked increase in the invasive and metastatic potential of MDA-MB-435LM cells in vitro and in vivo, accompanied by the up-regulation of matrix metalloproteinase-2 (MMP-2), MMP-9, transcription factor Ets-1, and RhoC expression in both mRNA and protein levels. Consistent with this observation, reduced AF1Q expression in MDA-MB-435HM cells by small interfering RNA (siRNA) resulted in a significant decrease in the invasive potential of MDA-MB-435HM cells in vitro and in the protein expression of MMP-2, MMP-9, Ets-1, and RhoC, compared with either parental or non-silencing control cells. These data provide functional evidence that oncogene AF1Q may be a novel mediator of metastasis promotion in human breast cancer through regulation of the MMP pathway and RhoC expression.

Blood Proteins↗

PubMed2006

Dominant-negative E-cadherin inhibits the invasiveness of inflammatory breast cancer cells in vitro.

E-cadherin is a transmembrane glycoprotein which mediates epithelial cell-to-cell adhesion function as a tumor suppressor and frequently loss of expression in a wide spectrum of human cancer. However, recent studies demonstrated that E-cadherin was always over-expressed in inflammatory breast cancer (IBC) specimen and cell lines, which is a clinical extreme malignancy of breast cancer. It is hypothesized that the gain and not the loss of the E-cadherin axis contributes to the IBC unique phenotype. To test this assumption, we generated dominant negative mutant E-cadherin high-expression inflammatory breast cancer cells by introduced dominant negative mutant E-cadherin (H-2kd-E-cad) cDNA into human IBC SUM149 cells. Our studies demonstrated that the ability of invasion of SUM149 cells was significantly inhibited by H-2kd-E-cad via down-regulation of MMP-1 and MMP-9 expression. The underlying signal pathway of MAPK phosphorylated Erk 1/2(P44/42) in H-2kd-E-cad-transfected SUM149 cells was significantly down-regulated compared to parental and mock contrast. Our studies provided further functional evidence as the gain of E-cadherin expression dedicated to the IBC malignant phenotype and the blockage of MAPK/Erk activation maybe a promising therapeutic target.

Breast Neoplasms↗

PubMed2006

The prevalence of BRCA1 and BRCA2 mutations in eastern Chinese women with breast cancer.

To investigate the prevalence of BRCA1 and BRCA2 mutations among Chinese patients, we studied 70 Shanghai cases with early onset breast cancer and affected relatives, and mutation screening was performed in the whole-gene sequence of BRCA1 and BRCA2 by polymerase chain reaction-based denaturing high-performance liquid chromatography. Six disease-causing mutations in BRCA1 (8.6%) and two in BRCA2 (2.9%) were detected, including four novel mutations that were all in the BRCA1 gene (3449insA, IVS17-1G>T, IVS21+1G>C and 5587-1del8). Additional sequence variants identified included 30 polymorphisms (18 in BRCA1 and 12 in BRCA2) and a novel mis-sense mutation of unknown significance in BRCA2 (5911G>C). The 9.5 and 2.4% patients with breast cancer diagnosed before the age of 35 were BRCA1- and BRCA2-mutation carriers, and the prevalence of BRCA1 and BRCA2 mutations in the families with two or more affected individuals were 12.1 and 3.0%, respectively. In these families, all the BRCA1 and BRCA2 mutations were detected in the families containing at least one case diagnosed under the age of 40, and in the families whose youngest patients were diagnosed before the age of 35, the prevalence of BRCA1 and BRCA2 were as high as 40 and 20%, respectively. Based on this information, we conclude that genetic testing should be performed among patients with early onset breast cancer (<40 years), especially combined with family history.

Adult↗

PubMed2006

Breast conservative therapy in east part of China: a retrospective cohort study.

PURPOSE: To compare the effects of breast conservative therapy (BCT) with modified radical mastectomy (MRM) in women with early stage breast cancer in the east part of China. We conducted a matched retrospective cohort study using data on patients derived from a prospectively collected breast cancer database. METHODS: We used the database that included patients who received MRM or BCT from 1995 to 2002 in our hospital. The match was conducted according to four variables: age at diagnosis, axillary lymph node status, hormone receptor status, and the dimension of tumor. The match ratio was 1:2. MRM group were patients who received MRM treatment (n=254). BCT group were patients who received BCT treatment (n=127). Median follow-up time for the BCT group and MRM group were 58 and 49 months, respectively. The differences of incidence of loco-regional recurrence, disease free survival, and overall survival at 5 years were compared. RESULTS: There were no significant differences in incidence of loco-regional recurrence, DFS and OS at 5 years between the two groups of patients. The incidence of loco-regional recurrence was 1.84% in MRM group and 3.39% in BCT group (P=0.55). The DFS in MRM and BCT patients were 91.57 and 86.04% (P=0.37); the OS in MRM and BCT patient were 97.57 and 96.73% (P=0.66). CONCLUSIONS: For appropriate breast cancer patients, classic lumpectomy plus axillary dissection and postoperative radiotherapy lead to excellent local control and good survival rate in our study. The BCT can result in the same effects as MRM in Chinese breast cancer patients with better cosmetic appearances.

Breast Neoplasms↗

PubMed2006

Identification of breast cancer metastasis-associated proteins in an isogenic tumor metastasis model using two-dimensional gel electrophoresis and liquid chromatography-ion trap-mass spectrometry.

To better understand the molecular mechanisms underlying breast cancer metastasis and search for potential markers for metastatic progression, we have developed a highly metastatic variant of human MDA-MB-435 breast cancer cell line through in vivo stepwise selection of pulmonary metastatic cells caused by parental MDA-MB-435 cells in the athymic mice. Comparative proteomic analysis using 2-DE and LC-IT-MS revealed that 102 protein spots were reproducibly altered more than three-fold between the selected variant and its parental counterpart. Eleven differentially expressed protein spots were identified with high confidence using SEQUEST with uninterpreted tandem mass raw data. Cathepsin D precursor, peroxiredoxin 6 (PDX6), heat shock protein 27 (HSP27), HSP60, tropomyosin 1 (TPM1), TPM2, TPM3, TPM4, 14-3-3 protein epsilon, and tumor protein D54 were up-regulated in the highly metastatic variant, whereas alpha B-crystalline (CRAB) was only detected in its parental counterpart. Differential expression was confirmed for four proteins including PDX6, CRAB, TPM4, and HSP60 by real-time quantitative PCR and Western blotting analysis in our model. Immunohistochemical analysis in 80 breast cancer donors demonstrated a significant association of TPM4 (p = 0.002), HSP60 (p = 0.001), PDX6 (p = 0.002) but not CRAB (p = 0.113) staining with the presence of lymph node metastasis. In addition, TPM4 staining was also associated with clinical stage (p = 0.000), but no significant association was found between TPM4, PDX6, CRAB, and HSP60 expression and tumor size, hormone receptor, and HER-2 status (p > 0.05). The functional implication of these identified proteins was also discussed. These proteomic data are valuable and informative for understanding breast cancer metastasis and searching for potential markers for metastatic progression.

Animals↗

PubMed2006

Enhanced expression of LKB1 in breast cancer cells attenuates angiogenesis, invasion, and metastatic potential.

LKB1 (also known as STK11) is a recently identified tumor suppressor gene whose mutation can lead to Peutz-Jeghers syndrome, which is characterized by gastrointestinal polyps and cancers of different organ systems. Approximately 30% of sporadic breast cancer samples express low levels of LKB1. This suggests that the LKB1 gene may be related to the tumorigenesis of breast cancer. We reintroduced LKB1 into MDA-MB-435 breast cancer cells that lack the LKB1 gene to investigate how overexpression of LKB1 affects tumor invasiveness and metastasis. Overexpression of the LKB1 protein in breast cancer cells resulted in significant inhibition of in vitro invasion. In vivo, LKB1 expression reduced tumor growth in the mammary fat pad, microvessel density, and lung metastasis. LKB1 overexpression was associated with down-regulation of matrix metalloproteinase-2, matrix metalloproteinase-9, vascular endothelial growth factor, and basic fibroblast growth factor mRNA and protein levels. Overexpression of the LKB1 protein in human breast cancer is significantly associated with a decrease in microvessel density. Our results indicate that LKB1 plays a negative regulatory role in human breast cancer, a finding that may lead to a new therapeutic strategy.

AMP-Activated Protein Kinase Kinases↗

PubMed2005

[Function and prognostic value of tumor suppressor gene LKB1 in human breast carcinoma].

OBJECTIVE: To study the function and prognostic value of the recently identified tumor suppressor gene LKB1 in human breast cancer. METHODS: Estrogen receptor-positive human breast cancer cells of MCF-7 line and estrogen receptor-negative human breast cancer cells of the lines MDA-MB-435 and MDA-MB-231 were cultured and tested for the LKB1 expression. Plasmid pcDNA4 TOPO HisMAX/LKB1 expressing LKB1 was constructed and transfected into the MDA-MB-435 cells. PCR and Western blotting were used to detect the expressions of LKB1 mRNA and protein. Flow cytometry was used to determine the cell cycle. PCR and Western blotting were used to detect the expressions of LKB1 mRNA and protein in 121 human breast cancer samples. The association with relapse free survival (RFS) and overall survival (OS) was assessed by univariate analysis (log-rank test and Kaplan-Meier method). RESULTS: Human breast cells of MCF-7 line expressed LKB1 and the cells of MDA-MB-435 and MDA-MB-231 lines did not. Flow cytometry showed that 40.9% of the MDA-MB-435 transfected with pcDNA4 TOPO HisMAX/LKB1 was at the G(1) stage, a proportion significantly higher than that of the control (18.3%). The expressions of cyclin D1 and cyclin E were significantly down-regulated and the expression of p21(WAF1/CIP1) was significantly up-regualed. LKB1 was lowly expressed in 43 out of the 121 cases of breast cancer (35.4%) and highly expressed in 78 cases (64.6%). Low expression of LKB1 was correlated with pathological grade (P = 0.013), cancer size (P = 0.001), status of estrogen receptor (P = 0.048), and status of lymph nodes metastasis (P = 0.003). Univariate analysis showed that low expression of LKB1 was significantly correlated with shorter RFS (P = 0.048) and low OS (P = 0.003). CONCLUSION: Reintroducing LKB1 into breast cell of the lines lacking LKB1 expression restores LKB1 activity and induces growth suppression by G(1) cell cycle block. The LKB1 mediated G(1) cell cycle arrest is caused by up-regulation of the expression of p21(WAF1/CIP1) in MDA-MB-435 breast cancer cells.

AMP-Activated Protein Kinase Kinases↗

PubMed2004

ERbeta exerts multiple stimulative effects on human breast carcinoma cells.

Recent studies of ERs in breast cancer have demonstrated the existence of ERbeta in addition to ERalpha. Some clinical data indicated that ERbeta had prognostic value for patient's survival, which suggested that ERbeta plays a key role in breast cancer development and metastasis. To test this hypothesis, we generated an ERbeta high-expression cell line by reintroduced human ERbeta cDNA into MDA-MB-435 cells. We demonstrated that ERbeta exerted multiple tumor-stimulative effects on human breast carcinoma cells both in vivo and in vitro. In in vitro studies, ERbeta was able to increase the proliferation and invasion of MDA-MB-435 cells significantly, while these effects were totally estradiol independent. Also, this stimulation was characterized by downregulation of p21 and upregulation of MMP-9, as well as transcriptional factor Est-1. In in vivo studies, we also demonstrated that ERbeta-transfected MDA-MB-435 cells grew much faster and had more pulmonary metastasis than mock or wild-type cells in nude mice. In ERbeta-transfected MDA-MB-435 xenografts, ERbeta caused significant reduction in p21 protein levels. Similar effects of ERbeta on MMP-9 and Ets-1 expression noted in vitro studies were also observed in the in vivo studies. These in vitro and in vivo studies indicated that ERbeta exerted multiple stimulative effects on breast cancer development and metastasis.

Animals↗

PubMed2004

Prognostic value of matrix metalloproteinases (MMP-2 and MMP-9) in patients with lymph node-negative breast carcinoma.

Twenty-five to thirty percent of patients with node-negative breast cancer are expected to relapse following surgery, therefore great efforts have been made to identify new prognostic markers that could be useful in defining patients for additional therapy. The expression of MMP-2 and MMP-9 has been associated with high potential of metastasis in several human carcinomas including breast cancer. In the present study we examined the prognostic value of immunoreactive MMP-2/MMP-9 protein in 270 consecutive lymph node negative cases who received radical mastectomy or modified radical mastectomy. Among the patients, 211 cases received adjuvant endocrine therapy and/or adjuvant chemotherapy. Using immunohistochemical assay, we found that 56.7% of the resected tumors were positive for MMP-2 whereas 59.6% of the samples were positive for MMP-9. Chi2 test demonstrated a significant direct association between MMP-2 and MMP-9 (p < 0.001); positive immunostaining of MMP-2 was significantly related to higher tumor grade (p < 0.001) and larger tumor size (p = 0.012); positive immunostaining of MMP-9 was significantly related to higher tumor grade (p = 0.002). In univariate analysis, using Cox-proportional hazard model we found MMP-2, MMP-9 and the co-expression of MMPs (MMP2/MMP9) were significantly associated with patients' relapse free survival (p = 0.016, 0.015 and 0.013 respectively) but not overall survival (p = 0.122, 0.320 and 0.091 respectively). Log-rank test also showed that MMP-2, MMP-9 or the co-expression of MMP2/MMP9 was unfavorable prognostic factor for relapse free survival but not overall survival. In subgroup analysis, we found MMPs were more prognostic for patients with no adjuvant treatment than for patients with adjuvant therapy. In multivariate analysis, using Cox-proportional hazard model we found co-expression of MMPs, larger tumor size and higher tumor grade were unfavorable for relapse free survival (p = 0.038, 0.007 and 0.015 for each). We concluded that MMP-2 and MMP-2 are unfavorable prognostic factors in breast cancer patients. They might be potential predictive factor for adjuvant systemic therapy. The co-expression of MMP-2 and MMP-9 has significantly prognostic value in node-negative patients.

Antineoplastic Agents, Hormonal↗

PubMed2003

The analysis of BRCA1 mutations in eastern Chinese patients with early onset breast cancer and affected relatives.

To study the BRCA1 mutations in eastern Chinese patients with early onset breast cancer and affected relatives, 41 patients' genomic DNA from peripheral mononuclear blood cells was studied by using single strand conformational polymorphism (SSCP) and DNA sequencing. The BRCA1 mutations were detected in the whole gene sequence. Three novel disease-causing mutations (c.582C>T, c.735C>T and c.2790delT) occurred in all the patients. Two occurred in the patients younger than 35 years old (9.1%) and one in the patients with affected relatives (5%). Additional sequence variants identified included a novel missense mutation of unknown significance and six polymorphisms. The prevalence of BRCA1 mutations in Chinese patients in Shanghai with early onset breast cancer is similar to that observed in western women, but the incidence of mutations in breast cancer patients in Shanghai with affected relatives isn't as high as that in western women.

Adult↗

PubMed2003

Addition of adjuvant tamoxifen to cyclophosphamide, methotrexate and 5-fluorouracil for premenopausal women with oestrogen receptor-positive breast cancer.

OBJECTIVE: To study the value of adjuvant tamoxifen (TAM) in premenopausal women with oestrogen receptor (ER)-positive breast cancer who received adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) polychemotherapy. METHODS: Four hundred and two premenopausal ER-positive breast cancer patients who received CMF chemotherapy between January 1990 and December 1999 were retrospectively studied. Disease-free survival (DFS) and overall survival (OS) were used to evaluate the clinical value of TAM therapy. The relationships between nodal status and TAM were also analysed. RESULTS: After a mean of 41 months of follow-up, 43 (13.7%) patients died of breast cancer and 68 (19.9%) patients suffered recurrence. There was a significant difference between TAM and non-TAM treatment groups for DFS (p=0.0058), but no significant difference for OS. For node-negative patients, there was no significant difference between the TAM and non-TAM treatment groups for either DFS or OS. For node-positive patients, the difference between TAM and non-TAM treatment groups was significant for both DFS and OS (p=0.0497 and p=0.0285, respectively). CONCLUSION: TAM resulted in additional benefit to premenopausal patients with node-positive ER-positive breast cancer who received the CMF polychemotherapy regimen.

Adult↗

PubMed2002

Curcumin exerts multiple suppressive effects on human breast carcinoma cells.

In our study, we present experimental evidence suggesting that curcumin exerts multiple different suppressive effects on human breast carcinoma cells in vitro. Our experiments demonstrate that curcumin's antiproliferative effects are estrogen dependent in ER (estrogen receptor)-positive MCF-7 cells, being more pronounced in estrogen-containing media and in the presence of exogenous 17-beta estradiol. Curcumin inhibits the expression of ER downstream genes including pS2 and TGF-beta (transforming growth factor) in ER-positive MCF-7 cells, and this inhibition is also dependent on the presence of estrogen. Curcumin also decreases ERE (estrogen responsive element)-CAT activities induced by 17-beta estradiol. In addition, we demonstrate that curcumin exerts strong anti-invasive effects in vitro that are not estrogen dependent in the ER-negative MDA-MB-231 breast cancer cells. These anti-invasive effects appear to be mediated through the downregulation of MMP-2 (matrix metalloproteinase) and the upregulation of TIMP-1 (tissue inhibitor of metalloproteinase), 2 common effector molecules that have been implicated in regulating tumor cell invasion. Our study also demonstrates that curcumin inhibits the transcript levels of 2 major angiogenesis factors VEGF (vascular endothelial growth factor) and b-FGF (basic fibroblast growth factor) mainly in ER-negative MDA-MB-231 cells.

Antineoplastic Agents↗

PubMed2002

The tumor suppressor gene LKB1 is associated with prognosis in human breast carcinoma.

PURPOSE: LKB1 (also called STK11) is a recently identified tumor suppressor gene in which its mutation can lead to Peutz-Jeghers syndrome, characterized by gastrointestinal polyps and cancers of different organ systems. Weak expression of this gene does occur at a certain frequency in sporadic breast cancer. This indicates that LKB1 gene may relate to the tumorigenesis of breast cancer. EXPERIMENTAL DESIGN: To investigate the function of the LKB1 gene in sporadic breast cancer, we reintroduced LKB1 into breast cancer cell lines which lack the LKB1 gene. Also, we examined the LKB1 protein expression in human breast cancer samples. RESULTS: We found that reintroducing LKB1 into breast cancer cell lines suppresses cell growth by G(1) cell cycle block. The LKB1-mediated G(1) cell cycle arrest is caused by up-regulation of the expression of p21(WAF1/CIP1) in breast cancer MDA-MB-435 cells. We also demonstrated that low LKB1 protein expression correlates with higher histological grade (P = 0.013), larger tumor size (P = 0.001), progesterone receptor status (P = 0.048), and presence of lymph node metastasis (P = 0.003). Furthermore, LKB1 low expression was associated with a higher relapse rate (P = 0.002) and a worse OS (P = 0.008). CONCLUSIONS: LKB1 plays a role in tumor suppressor function in human breast cancer. LKB1 expression may be a useful prognostic marker in human breast cancer.

AMP-Activated Protein Kinase Kinases↗

PubMed2002

Retraction.

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Retraction Notice↗

PubMed2000

Significance of Apoptosis and Apoptotic-Related Proteins, Bcl-2, and Bax in Primary Breast Cancer.

Apoptosis and expression of apoptosis-regulating proteins, Bcl-2 and Bax, have been observed in human breast carcinomas. The authors investigated whether expression of Bcl-2 and Bax proteins and apoptotic index (AI) had significance in cases of primary breast cancer. The authors evaluated Bcl-2 and Bax immunoreactivity and AI in primary breast cancers with the ApopTag method in 91 breast cancer patients retrospectively with long-term follow-up (median 60 months). Bcl-2 expression was seen in 60 (65.9%) cases and Bax expression was observed in 59 (64.8%) cases. Increased Bcl-2 and absence or low Bax immunoreactivity were significantly associated with low AI, high tumor grade, axillary lymph node involvement, postoperative recurrence, and metastasis. Thirty-five (38.5%) samples expressed high AI, which correlated with low tumor grade, absent axillary lymph node metastasis, and low levels of Bcl-2 with Bax overexpression. In univariate analysis, the variables associated with short relapse-free survival (RFS) and overall survival (OS) were large tumor size, axillary lymph node involvement, high histologic grade, low AI, high Bcl-2 expression, and absence or low Bax expression. In multivariate analysis, only Bcl-2 expression, lymph node status, and histologic grade were of independent prognostic value with respect to RFS and OS. Because the vast majority of the patients in this study received chemotherapy, it can be concluded that these apoptotic markers were also predictive of response to chemotherapy. Immunostaining of apoptosis-related genes, Bcl-2 and Bax, together with AI, may stratify high- versus low-risk breast cancer patients.

Journal Article↗

PubMedDate not supplied

The expression of ER beta protein correlates with vascular endothelial growth factor and its prognostic significance in human breast cancer.

Although cloning of ER beta has prompted a reevaluation of the role of ERs in human breast cancer and there have been many studies focusing on the clinical value of ER beta detection, however, few reports evaluated the prognostic significance of ER beta based on follow-up data. The VEGF gene transcription may be mediated by different ER subtypes directly. The aim of this study was to evaluate the relationship of angiogenesis factor VEGF with different ER subtypes and the prognostic value of ER beta and VEGF in 116 human breast cancer patients. Of these patients, 40 (34.5%) were ER beta protein high expressed and 76 (65.5%) were ER beta protein low expressed. When correlated the ER beta protein levels with other clinical characteristics, statistical significance (p<0.05) was found between ER beta protein expression and menopausal status, and tumor grade. No significance was found between ER beta protein level and node status, stage, or tumor size. Inverse relationship was found between ER beta protein expression and PR status (p<0.05). When comparing the VEGF levels with different ER subtypes a significant difference between ERs and VEGF was found. In ER beta protein high expression group, the VEGF protein was highly expressed (p<0.01), inverse relationship was also found between ER alpha and VEGF. In univariate analysis ER alpha, ER beta and VEGF levels had prognostic value for both relapse-free survival and overall survival (p<0.05). However, in a multivariate study, ER beta and ER alpha protein levels lost the prognostic value either to relapse-free survival or to overall survival. Only VEGF levels acted as an independent prognostic factor to disease-free survival. The result suggested that ER beta protein may have important prognostic value in human breast cancer patients. VEGF expression may be mediated through different ER subtypes.

Adult↗