Breast Neoplasms: Shen ZZ

Wang LP, Shen KW, Shen ZZ. · No affiliation provided · Zhonghua Zhong Liu Za Zhi. · Pubmed #16875618 No free full text.

This publication has no abstract.

Hortobagyi GN, de la Garza Salazar J, Pritchard K, Amadori D, Haidinger R, Hudis CA, Khaled H, Liu MC, Martin M, Namer M, O'Shaughnessy JA, Shen ZZ, Albain KS, Anonymous00349. · The University of Texas MD Anderson Cancer Center, Houston, 77030, USA. · Clin Breast Cancer. · Pubmed #16381622 No free full text.

Abstract: Breast cancer is the most common type of cancer and the most common cause of cancer-related mortality among women worldwide. However, the burden is not evenly distributed, and, according to the best available data, there are large variations in the incidence, mortality, and survival between different countries and regions and within specific regions. Many complex factors underlie these variations, including population structure (eg, age, race, and ethnicity), lifestyle, environment, socioeconomic status, risk factor prevalence, mammography use, disease stage at diagnosis, and access to high-quality care. We review recent breast cancer incidence and mortality statistics and explore why these vary so greatly across the world. Further research is needed to fully understand the reasons for variations in breast cancer outcomes. This will aid the development of tailored strategies to improve outcomes in general as well as the standard of care for underserved populations and reduce the burden of breast cancer worldwide.

Shen ZZ, Liu GY, Su FX, He PQ, Yang MT, Shi JY, Sheng Y, Zou Q, Li YF. · Department of Breast, Cancet Hospital, Fudan University, Shanghai 200032, China. · Zhonghua Zhong Liu Za Zhi. · Pubmed #15946557 No free full text.

Abstract: OBJECTIVE: To investigate the clinical response, pathological complete response (pCR), tumor resection rate and safety of neoadjuvant chemotherapy with docetaxel and epirubicin (ET) for locally advanced breast cancer (LABC). METHODS: From March to December 2001, 40 women with LABC, aged from 28-67 (medium 48) years were alloted. Twenty patients had clinical stage IIIa disease, 15 had stage IIIb disease and 5 stage IV patients who had ipsilateral sura-clavicular metastasis. The dose was: epirubicin (E) 60 mg/m2, docetaxel (T) 75 mg/m2 every 3 weeks, with G-CSF given preventively. After 2 cycles of ET, a pilot clinical response evaluation was performed by investigators for each patient to decide if she should receive another 1-2 cycles of ET before surgery or radiation therapy. RESULTS: Thirty-eight patients received 2-3 cycles of ET regimen. The pCR, clinical complete response (cCR) and clinical partial response (cPR) rates were 15.0%, 20.0% and 52.5%, respectively. Tumor resection rate in this group was 92.5%. Incidence of III/IV Grade neutropenia was 8.4%/14.0% of cycles, and 3 patients suffered from neutropenia with fever. Non-hematological adverse events were alopecia, nausea, vomiting, fluid retention, myalgia, arthralgia and nail disorders, which were mild to moderate. CONCLUSION: Neo-adjuvant chemotherapy with a combination of docetaxel and epirubicin is effective and well tolerated by women with locally advanced breast cancer.

Shen KW, Wu J, Lu JS, Han QX, Shen ZZ, Nguyen M, Barsky SH, Shao ZM. · Department of Surgery, Cancer Hospital/Cancer Institute, Shanghai Medical University, Shanghai, 200032, P. R. China. · Surg Endosc. · Pubmed #11727147 No free full text.

Abstract: BACKGROUND: Breast cancer and precancer are thought to originate in the lining of the milk duct, but until recently, we have not had direct access to this area other than in tissue removed blindly by core biopsy or fine-needle aspiration. Fiberoptic ductoscopy (FDS) is an emerging technique that allows direct visual access of the ductal system of the breast through nipple orifice cannulation and exploration. To date, this technique has been used only in pilot studies. Previously, we have demonstrated that fiberoptic ductoscopy in patients with and without nipple discharge is a safe and effective means of visualizing the intraductal lesion. When combined with cytology, it is a screening technique that has high predictive value. METHODS: We applied ductoscopy to 415 women with nipple discharge with the specific intent of detecting those patients with nipple discharge who had intraductal carcinoma (DCIS) as the basis of their discharge. RESULTS: In this cohort of patients, ductoscopy was successful in visualizing an intraductal lesion in 166 patients (40%). In these cases, ductal lavage following ductoscopy increased the yield of cytologically interpretable ductal epithelial cells 100-fold compared to discharge fluid alone. In the majority of these patients, FDS examination detected lesions that had the appearance of typical papillomas. However, in 10 patients, the intraductal lesion exhibited one of several atypical features, including bleeding, circumferential obstruction, and gross fungating projections. In eight of these patients, the subsequent histopathology turned out to be DCIS. In two of these eight patients, endoscopic biopsy revealed cytologically malignant cells; in two others, ductal lavage (washings) revealed cytologically malignant cells. In three additional patients, although FDS examination uncovered a typical papilloma that was not biopsied, ductal lavage (washings) revealed cytologically malignant cells. On surgical pathology review of the extirpated lesions, all 11 patients were subsequently shown to have DCIS. Of these 11 cases of DCIS that were initially detected with a combination of FDS and ductal lavage cytology, six were completely negative on mammogram and physical exam. CONCLUSION: Although nipple discharge is an unusual presentation for DCIS, in patients with nipple discharge, FDS with ductal lavage cytology is a useful technique for diagnosing DCIS prior to definitive surgery.

Shao ZM, Li J, Wu J, Han QX, Shen ZZ, Fontana JA, Barsky SH. · Department of Surgery, Cancer Hospital, Shanghai Medical University, China. · Breast Cancer Res Treat. · Pubmed #10369072 No free full text.

Abstract: The use of neo-adjuvant chemotherapy (often referred to as pre-operative or primary chemotherapy) represents a major change in the management of breast cancer as a systemic disease. Laboratory studies have shown that many anti-cancer agents with differing modes of action achieve cytotoxic effects by inducing apoptosis. In this study, we investigated the induction of apoptosis by neo-adjuvant chemotherapy in human breast cancer. The aim was to determine whether a correlation existed between post chemotherapy apoptotic index (AI) and clinical response and patients' survival. Our results indicate that apoptosis is induced by neo-adjuvant chemotherapy and that the response is variable. Our data show that post chemotherapy AI correlated with clinical response and increased patient survival, including both relapse (disease) free survival and overall survival. Post-neo-adjuvant chemotherapy AI levels in primary breast cancer may possibly predict an individual patient's overall response.

Feng LY, Ou ZL, Wu FY, Shen ZZ, Shao ZM. · Department of Oncology, Fudan University, Shanghai, People's Republic of China. · Clin Cancer Res. · Pubmed #19383822 No free full text.

Abstract: PURPOSE: The biological axes of chemokines and chemokine receptors, such as CXCR4/CXCL12, CCR7/CCL19 (CCL21), CCR9/CCL25, and CXCR5/CXCL13, are involved in cancer growth and metastasis. This study is aimed at the potential regulatory role of atypical chemokine binder CCX-CKR, as a scavenger of CCL19, CCL21, CCL25, and CXCL13, in human breast cancer. EXPERIMENTAL DESIGN: The role of CCX-CKR in human breast cancer was investigated in cell lines, animal models, and clinical samples. RESULTS: Overexpression of CCX-CKR inhibited cancer cell proliferation and invasion in vitro and attenuated xenograft tumor growth and lung metastasis in vivo. CCX-CKR can be regulated by cytokines such as interleukin-1beta, tumor necrosis factor-alpha, and IFN-gamma. Lack or low expression of CCX-CKR correlated with a poor survival rate in the breast cancer patients. A significant correlation between CCX-CKR and lymph node metastasis was observed in human breast cancer tissues. CCX-CKR status was an independent prognostic factor for disease-free survival in breast cancer patients. CONCLUSION: We showed for the first time that CCX-CKR is a negative regulator of growth and metastasis in breast cancer mainly by sequestration of homeostatic chemokines and subsequent inhibition of intratumoral neovascularity. This finding may lead to a new therapeutic strategy against breast cancer.

Liu ZB, Wu J, Ping B, Feng LQ, Di GH, Lu JS, Shen KW, Shen ZZ, Shaol ZM. · Department of Breast Surgery, Breast Cancer Institute, Fudan University Shanghai, Shanghai, Republic of China. · Tumori. · Pubmed #19366057 No free full text.

Abstract: AIMS AND BACKGROUND: To evaluate the immunohistochemical characterization of CK5/6 and CK17 and whether the expression level of the two markers was correlated with clinical outcome or pathological feature in triple negative (ER-, PR-, HER-2-) patients with breast cancer. METHODS AND STUDY DESIGN: We carried out an immunohistochemical assay for CK5/6 and CK17 markers on formalin-fixed invasive carcinoma samples from 112 patients who were diagnosed between 2000 and 2002. All of them had an immunohistochemical triple negative status and follow-up information available. RESULTS: Of the 112 patients characterized by triple negative immunohistochemical status, 82 (73.2%) were disease free with no relapse or metastasis. In total, CK5/6 and CK17 were both determined positive in 33.9% (38/112) of the 112 tumor samples, and 46.4% (52/112) were regarded as positive for CK5/6 or CK17. The Kaplan-Meier curve showed that positive staining for CK5/6, CK17, or CK which means CK5/6 positive or CK17 positive, was associated with worse disease-free survival (P = 0.020, P = 0.032, P = 0.003), and positive staining for CK5/6 or CK was associated with worse overall survival (P = 0.027, P = 0.015). When we considered 91 patients whose pathological type was invasive ductal carcinoma, we found that there was also an association between CK5/6 or CK17 immunostaining and high grade (P = 0.030). In addition, these two markers were also associated with axillary lymph node status (P = 0.044). The Cox regression multiple-factor analysis showed that pathological stage, grade and expression of CK were the factors affecting both disease-free and overall survival, whereas age and menopausal status were independent factors affecting disease-free and overall survival, respectively. CONCLUSIONS; Positive staining for CK5/6 or CK17 was associated with a worse prognosis, high tumor grade and positive axillary lymph nodes.

Ling H, Liu GY, Lu JS, Love S, Zhang JX, Xu XL, Xu WP, Shen KW, Shen ZZ, Shao ZM. · Department of Surgery, Cancer Hospital, Fudan University, Shanghai, China. · Breast J. · Pubmed #19292803 No free full text.

Abstract: Fiberoptic ductoscopy (FDS)-guided intraductal biopsy is a minimally invasive technique developed to obtain pathologic diagnoses for patients with spontaneous nipple discharge. We performed biopsies of 53 intraductal lesions from March 2006 to April 2007 followed by surgical microdochectomy. FDS-guided intraductal biopsy was shown to be a minimally invasive, safe, and convenient technique with a high ability (90.6%) to get adequate samples. Twenty-seven solitary papillomas, 12 multiple intraductal papilloma, five ductal hyperplasia, three ductal carcinoma in situ, and one invasive ductal carcinoma were diagnosed. Compared with conventional microdochectomy, FDS-guided intraductal biopsy can significantly increase the detection rate of solitary papilloma (40.7% versus 92.6%, p < 0.05). It should be a routine procedure after intraductal lesion found by screening FDS. Since it would underestimate all multiple intraductal papilloma and some (50%) cancer, microdochectomy is inevitable if biopsies show atypical ductal hyperplasia.

Hu Z, Li WF, Liu XY, Zhang B, Cao MZ, Wang YS, Zhao L, Song CG, Lu JS, Wu J, DI GH, Shen KW, Han QX, Shen ZZ, Huang W, Shao ZM. · Breast Cancer Institute, Cancer Hospital/Cancer Institute, Fudan University, Shanghai 200032, China. · Zhonghua Yi Xue Za Zhi. · Pubmed #19087709 No free full text.

Abstract: OBJECTIVE: To study the BRCA1/2 gene mutation frequency and characteristics in Chinese familial breast cancer patients. METHODS: Denaturing high-performance liquid chromatography (DHPLC) and following DNA sequencing in BRCA1/2 gene whole coding region and exon-intron splicing sites were performed in the specimens obtained during operation from 115 probands of familial breast cancer from 4 breast cancer centers in China. RESULTS: Fourteen cases of gene mutation (11 in BRCA1 and 3 in BRCA2) were found in the 115 breast cancer specimens with an overall mutation rate of 12.2%. After stratification with number of breast cancer patients in family, the frequency of mutation did not change significantly. The average age of disease onset of the families carrying BRCA1/2 mutations was significantly younger than that of the families without mutations (P < 0.01), and the higher the number of young patients in family, the higher the mutation rate. CONCLUSION: In Chinese familial breast cancer patients, age of disease-onset is an effective predictive factor of BRCA1/2 mutation, however, the predictive effect of the number of affective relatives in family is not good.

Ma CD, Chen CM, Chen XS, Liu GY, Di GH, Wu J, Lu JS, Yang WT, Chen JY, Shao ZM, Shen ZZ, Shen KW. · Department of Breast Surgery, Cancer Hospital, Fudan University, Shanghai, P.R. China. · Anticancer Res. · Pubmed #19031963 No free full text.

Abstract: BACKGROUND: The purpose of this study was to evaluate retrospectively the efficacy and safety of neoadjuvant chemotherapy with vinorelbine-containing regimens in elderly patient with locally advanced breast cancer (LABC). PATIENTS AND METHODS: From 2002 to 2006, 14 female elderly patients with LABC underwent neoadjuvant chemotherapy with vinorelbine-containing regimens. Vinorelbine alone or in combination with pirarubicin/epirubicin was administered every 3 weeks (25 mg/m2, i.v., day 1 and day 8). All 14 patients received 2-6 cycles of chemotherapy. RESULTS: The median age was 68.5 years (range 65 to 78 years). Six patients had stage IIIA breast tumor, 7 stage IIIB and 1 stage IIIC. There was 1 complete response and 10 partial responses, with an overall response rate of 78.57%, and stable disease in 3 patients (21.43%); there were no patients with progressive disease before surgery. After a median follow-up of 35 months, the estimated 3-year disease-free and overall survival rates were 57% and 69%, respectively. CONCLUSION: The results of the current study showed that vinorelbine-containing neoadjuvant chemotherapy was effective and well-tolerated in elderly patients with LABC.

Wu J, Di GH, Chen TW, Qi FZ, Shen KW, Han QX, Shen ZZ, Shao ZM. · Department of Breast Surgery, Cancer Hospital, Fudan University, Shanghai 200032, China. · Zhonghua Wai Ke Za Zhi. · Pubmed #18953926 No free full text.

Abstract: OBJECTIVE: To evaluate the oncologic safety, indications and aesthetic results for skin-sparing mastectomy (SSM) and immediate breast reconstruction (IBR). METHOD: One hundred and twenty-nine breast cancer patients treated by SSM + IBR from October 1999 to May 2007 were reviewed. Reconstructive techniques included latissimus dorsi flaps (38 patients), implants only (2 patients), latissimus dorsi flaps plus implants (61 patients), pedicled transverse rectus abdominis myocutaneous (TRAM) flaps (25 patients) and deep inferior epigastric artery perforator (DIEP) flaps (3 patients). Aesthetic results were judged by patients' self-evaluation. RESULTS: Mean duration of hospitalization was 18.6 days. Time of first chemotherapy was 5.2 days after operation. Eleven patients (11/63, 17.5%) developed capsular contracture and 24 patients (24/99, 24.2%) developed seroma in the donor site. Nine patients (9/28, 32.1%) developed partial fat necrosis in TRAM and DIEP flaps. The satisfaction with the aesthetic results of the reconstructive breast was significantly lower in irradiated patients than non-irradiated ones. Median follow-up time was 11 months. Five patients developed local recurrence and 7 patients with metastasis. CONCLUSIONS: SSM with IBR can be used for the 0 to II a stage breast cancer patients, with surgical oncologic and aesthetic satisfaction. Radiotherapy has an adverse effect on the reconstructive breast. Delayed or delayed-immediate reconstructions are recommended for patients indicated to postoperative radiotherapy.

Liu ZB, Liu GY, Yang WT, Di GH, Lu JS, Shen KW, Shen ZZ, Shao ZM, Wu J. · Department of Breast Surgery, Cancer Hospital/Cancer Institute, Fudan University, 399 Ling-Ling Road, Shanghai, P.R. China. · Oncol Rep. · Pubmed #18813844 No free full text.

Abstract: Comparative studies on the clinical features and outcomes of triple-negative subgroups to human epidermal growth factor receptor-2 (HER-2) overexpression, and luminal A and B subgroups in lymph node-negative breast cancer patients, are important to correctly evaluate clinical prognosis. A total of 1132 Chinese breast cancer patients were enrolled in a retrospective analysis. We characterized and identified prognostic information in the triple-negative subgroup [estrogen receptor (ER)-, progesterone receptor (PR)- and HER-2-negative] and compared that to HER-2 overexpression, and the luminal A and B subgroups. By using immunohistochemical staining, the triple-negative subgroup showed 17% (193/1132) in the whole group. However, HER-2 overexpression, and the luminal A and B subgroups were 11.2, 47.9 and 23.9%, respectively. Tumors in the triple-negative subgroup showed a higher histological grade (P=0.025) and lower invasive ductal carcinoma (P=0.007), compared to the three subgroups. More patients in the luminal A subgroup had received adjuvant chemotherapy (P=0.007). The difference of disease-free survival rates among the four subgroups was significant (P=0.0001). The P-value for overall survival was 0.0598. No significant difference among the four subgroups in lymph node-positive and non-chemotherapy breast cancers was found. From our data the poor clinical outcomes were independent of age, histological grade, tumor size, lymph nodal status, chemotherapy and clinical stages. Our data suggest that the triple-negative subgroup exhibits a distinct poor clinical outcome, especially in lymph node-negative Chinese breast cancer patients.

Wu FY, Ou ZL, Feng LY, Luo JM, Wang LP, Shen ZZ, Shao ZM. · Department of Breast Surgery, Breast Cancer Institute, Fudan University, 399 Ling-Ling Road, Shanghai 200032, China. · Mol Cancer Res. · Pubmed #18708360 No free full text.

Abstract: Chemokine binding protein D6 is a promiscuous decoy receptor that can inhibit inflammation in vivo; however, the role it plays in cancer is not well known yet. In this study, we showed for the first time that human breast cancer differentially expressed D6 and the expression could be regulated by some cytokines. More importantly, overexpression of D6 in human breast cancer cells inhibits proliferation and invasion in vitro and tumorigenesis and lung metastasis in vivo. This inhibition is associated with decreased chemokines (e.g., CCL2 and CCL5), vessel density, and tumor-associated macrophage infiltration. Furthermore, D6 expression is inversely correlated to lymph node metastasis as well as clinical stages, but positively correlated to disease-free survival rate in cancer patients. Therefore, D6 plays a negative role in the growth and metastasis of breast cancer.

Yu KD, Di GH, Wu J, Lu JS, Shen KW, Liu GY, Shen ZZ, Shao ZM. · Department of Breast Surgery, Cancer Hospital/Cancer Institute, Fudan University, 200032 Shanghai, China. · J Cancer Res Clin Oncol. · Pubmed #18488249 No free full text.

Abstract: PURPOSE: Most breast cancer patients with estrogen receptor-negative/progesterone receptor-positive (ER-/PgR+) tumors are premenopausal cases, with few alternatives of adjuvant endocrine therapy but tamoxifen (TAM). The efficacy of adjuvant TAM on ER-/PgR+ patients is still controversial. In this study, we evaluated the efficacy of adjuvant TAM on patients with ER-/PgR+ tumors. METHODS: Among all 1,836 consecutive patients with operable primary breast cancer, 798 cases were with ER+/PgR+ tumors and 205 with ER-/PgR+ tumors. By sub-grouping the patients according to ER/PR phenotypes and whether the patients had been treated with adjuvant TAM therapy or not, we investigated the differences of survivals between groups. RESULTS: Patients with ER-/PgR+ tumors were younger than those with ER+/PgR+ tumors (P = 0.021), and were mainly premenopausal (P = 0.013). ER-/PgR+ patients were related to more involved lymph nodes and later stage. In the absence of TAM treatment, ER+/PgR+ group had a similar survival to ER-/PgR+ group in terms of 5-year disease-free survival (DFS), as well as overall survival (OS). After TAM treatment, both groups had increased survival rates comparing with the baseline of non-TAM-treated groups. Moreover, significant survival differences were then observed between TAM-treated ER+/PgR+ group and TAM-treated ER-/PgR+ group either in DFS (P = 0.016) or OS (P = 0.007). Of the TAM-treated patients, by sub-dividing the chemotherapy-treated population into CMF (cyclophosphamide, methotrexate and 5-fluorouracil) group and CA(E)F (cyclophosphamide, doxorubicin/epirubicin and 5-fluorouracil) group, we found that ER-/PgR+ group got more benefits from CMF regimen than from CA(E)F. Subpopulation treatment effect pattern plot (STEPP) analysis showed that the ER-/PgR+ group had an obvious worse survival than ER+/PgR+ group in younger patients (<55 years). Axillary lymph nodes involvement was the only independent prognostic factor for ER-/PgR+ group. CONCLUSIONS: Our results indicate that patients with ER-/PgR+ tumors are mainly premenopausal and young. Although patients with ER-/PgR+ tumors are generally considered as candidates for endocrine therapy clinically, the ER-/PgR+ group gains less benefits from adjuvant TAM treatment than ER+/PgR+ group.

Rao NY, Hu Z, Li WF, Huang J, Ma ZL, Zhang B, Su FX, Zhou J, Di GH, Shen KW, Wu J, Lu JS, Luo JM, Yuan WT, Shen ZZ, Huang W, Shao ZM. · Department of Oncology, Breast Cancer Institute, Cancer Hospital, Shanghai Medical College, Fudan University, Shanghai, PR China. · Breast Cancer Res Treat. · Pubmed #18343994 No free full text.

Abstract: PURPOSE: Our aim was to find an appropriate method to estimate the likelihood that a family history of cancer was a result of a mutation in the BRCA1 or BRCA2 genes. We also compared the performance of the established method with three different methods (Couch, Sh-E and BRCApro) to identify an alternative strategy for genetic council targeted to the specified population. PATIENTS AND METHODS: The family history as well as individual information of two hundred unrelated probands who had completed BRCA1 and BRCA2 mutation screening was analyzed to assess the likelihood of a pathogenic mutation. A model was developed by empirical method. The performance of this model was validated in a separate patient cohort compared with BRCApro. RESULTS: Several factors were associated with mutations in univariate analysis and a logistic model was devised to estimate the probability for a proband of harboring a mutation in BRCA1 and/or BRCA2. Using a greater than 10% probability threshold, the highest accuracy was achieved by the established model when compared to other three models, presenting the highest sensitivity, PPV, NPV and area under ROC curve. The empirical model showed a better ROC curve compared to BRCApro in the verification cohort. CONCLUSION: A probability model targeted to Han Chinese population should be a useful tool in the genetic counseling for the specified ethnic. Its ability to predict BRCA2 mutation carriers needs to be improved.

Wang JS, Wang FB, Zhang QG, Shen ZZ, Shao ZM. · Department of Oncology, Breast Cancer Institute, Cancer Hospital, Fudan University, Shanghai 200032, PR China. · Mol Cancer Res. · Pubmed #18337447 links to  free full text

Abstract: In addition to the functions of transporting melanosome in melanocytes and releasing contents of lytic granules in CTLs, Rab27A was recently shown to be involved in exocytosis of insulin and chromaffin granules in endocrine cells; it was also reported to be expressed in an exceptionally broad range of specialized secretory cells. As autocrine and paracrine cytokines are essential for invasion and metastasis in some solid tumors, blocking them may be an effective strategy to prevent tumor dissemination. In the present study, we show that Rab27A is associated with invasive and metastatic potentials of human breast cancer cells. The overexpression of Rab27A protein redistributed the cell cycle and increased the invasive and metastatic abilities in breast cancer cells both in vitro and in vivo. We also certified that Rab27A conferred the invasive and metastatic phenotypes on breast cancer cells by promoting the secretion of insulin-like growth factor-II (IGF-II), which regulates the expression of p16, vascular endothelial growth factor, matrix metalloproteinase-9, cathepsin D, cyclin D1, and urokinase-type plasminogen activator. These data provide functional evidence that Rab27A acts as a novel mediator of invasion and metastasis promotion in human breast cancer cells, at least in part, through regulating the secretion of IGF-II, suggesting that synergistic suppression of Rab27A and IGF-II activities holds a promise for preventing breast cancer invasion and metastasis.

Li LF, Xu XJ, Zhao Y, Liu ZB, Shen ZZ, Jin WR, Shao ZM. · Department of Oncology, Breast Cancer Institute, Cancer Hospital/Cancer Institute, Shanghai Medical College, Institutes of Biomedical Science, Fudan University, 270 Dong'an Road, Shanghai, 200032, P.R. China. · Breast Cancer Res Treat. · Pubmed #18278552 No free full text.

Abstract: Gene expression data has in recent years demonstrated the superior capacity to predict the prognosis of breast cancer patients unreceiving adjuvant chemotherapy comparing to the information available from traditional clinical and pathological sources. Meanwhile, adjuvant chemotherapy can significantly improve survival of breast cancer. It would be inappropriate to ignore its effect on prognosis. We hypothesized that an integrated gene expression profile can predict the prognosis of breast cancer patients receiving chemotherapy. Therefore, we screened the specific gene markers and constructed an integrated 24-gene signature by low-density microarray including the "poor signature" and genes related to resistance to chemotherapy. The gene signature stratified correctly patients into good prognosis group and poor prognosis group. In addition, the Kaplan-Meier analyses for disease-free survival as a function of the 24-gene signature showed highly significant differences between the two groups (Log Rank test P < 0.0001 = Univariate and multivariate Cox's proportional-hazards regression analyses indicated that the signature represents the strongest independent prognostic factor for breast cancer patients. When compared with single signature, such as Oncotype DX and 70 poor signature, the integrated signature showed more predominant power of predication in breast cancer patients receiving chemotherapy. Such integrated signature will critically aid clinical decision making at the level of individualization for most breast cancer patients receiving chemotherapy.

Fan J, Yin WJ, Lu JS, Wang L, Wu J, Wu FY, Di GH, Shen ZZ, Shao ZM. · Department of Breast Surgery, Cancer Hospital/Cancer Institute, Fudan University, 399 Ling-Ling Road, 200032, Shanghai, People.s Republic of China. · J Cancer Res Clin Oncol. · Pubmed #18264725 No free full text.

Abstract: PURPOSE: Estrogen receptor alpha (ER alpha) mediates the growth stimulation of estrogen in breast cancer cells and is a useful predictive factor for response to endocrine therapy. It is reported that ER alpha was induced in ER alpha negative breast cancer cells by both DNA methyltransferase-1 (DNMT1) inhibitor 5-aza-2'-deoxycytidine (AZA) and histone deacetylase (HDAC) inhibitor trichostatin A (TSA). However, whether the breast cancer cells with induced ER alpha restore response to endocrine therapy requires to be further researched. PATIENTS AND METHODS: Reverse transcriptase-polymerase chain reaction (RT-PCR) method was used to explore the change in the mRNA of ER alpha, PR and pS2 in the ER alpha negative breast cancer cells MDA-MB-435 treated with two chemicals (AZA + TSA). Water-soluble tetrazolium salt-8 (WST-8) method was used to study the proliferation rate of the breast cancer cells. Flow cytometer (FCW) was used to analyze the distribution of cell cycle of these breast cancer cells. Some xenograft models in nude mice were used to further study the results we found in vitro. RESULTS: In this study we observed that the mRNA of ER alpha, PR and pS2 in the ER alpha negative breast cancer cells MDA-MB-435 was re-expressed by treatment with AZA + TSA. The proliferation assay analysis showed AZA + TSA suppressed the proliferation of MDA-MB-435 cells, which were further suppressed by addition of 4-OH Tamoxifen (4-OHT). On the contrary, the proliferation of cells treated with 4-OHT alone showed no difference compared with the vehicle control. Cell cycle analysis showed AZA + TSA treated cells showed S phase arrest, which was partially attenuated by addition of estradiol (E2); furthermore, the effect of E2 on stimulation of cell cycle could be reversed by 4-OHT in the treated cells with induced ER alpha. In vivo experiment xenograft volume of MDA-MB-435 cells treated with AZA + TSA was smaller than that of the control (P < 0.01), and the xenograft of AZA + TSA treated cells was further suppressed by ovariectomy (P < 0.01). CONCLUSIONS: Our data indicate that DNMT1 inhibitor AZA and HDAC inhibitor TSA play important roles in restoring sensitivity of the ER alpha negative breast cancer cells to endocrine therapy in vitro and in vivo.

Zhou LH, Yin WJ, Lu JS, DI GH, Wu J, Shen KW, Han QX, Shen ZZ, Shao ZM. · Department of Breast Surgery, Cancer Hospital, Fudan University, Shanghai 200032, China. · Zhonghua Yi Xue Za Zhi. · Pubmed #18167267 No free full text.

Abstract: OBJECTIVE: To compare the differences in the clinicopathological and molecular biological features between the breast cancer patients with estrogen receptor (ER)+/progesterone receptor (PR)+ or ER+/PR- tumors. METHODS: The clinicopathological data of 3124 female breast cancer patients with known ER/PR expression status, 2220 being ER+/PR+ and 904 being ER+/PR-, and 1484 being ER-/PR-, were analyzed retrospectively. Immunohistochemistry was used to detect the expression of c-erb and cathepsin D in the tumor specimens. RESULTS: The average peak onset age was 50 years in both the ER+/PR+ and ER+PR- patients, and the mean age of the ER+/PR+ patients was 52.40 years, not significantly different from that of the ER-/PR- patients (52.57 years, P = 0.709). The peak onset age of the ER+ patients was 50 years, significantly higher that that of the ER- patients (48 years, P = 0.001), and the mean age of the ER+ patients was 52.46 years, significantly higher than that of the ER- patients (51.42 years, P = 0.001). Univariate analysis showed that ER+/PR- tumors tended to be larger. 24.8% of the ER+/PR- patients had 4 or more metastatic lymph nodes, a rate significantly higher than that of the ER+/PR- patients (20.7%, P = 0.004). The tumors of 18% of the ER+/PR- patients were at the grade III, a rate significantly higher than that of the ER+/PR+ patients (13.5%, P = 0.008). The strong positivity rate of the ER+/PR+ tumors was 23.4%, ignorantly higher than hat of the ER+/PR- tumors (11.2%, P = 0.000). The c-erB-2 positive rate of the ER+/PR+ tumors was 19.7%, significantly lower than that of the ER+/PR- tumor group (28.7%, P = 0.000). The cathepsin D positive rate of the ER+/PR- group was 76.9%, significantly higher than that of the ER+/PR- group (71.9%, P = 0.005). Multivariate analysis indicated that positive PR expression was associated with the level of ER (OR = 1.792, 95% CI = 1.484 - 2.164, P = 0.000), cathepsin D (OR = 1.380, 95% CI = 1.023 - 1.862, P = 0.035) and c-erbB-2 (OR = 0.639, 95% CI = 0.463 - 0.883, P = 0.007). CONCLUSION: ER+/PR+ and ER+/PR- tumors may have identical etiology. The mechanism of whether PR is expressed in ER+ breast cancer may be caused by different factors, which causing many different aspects. According to these differences, new target of therapy may provide the possibility of improving the response and prognosis for patients with ER+/PR- tumors.

Chang XZ, Li DQ, Hou YF, Wu J, Lu JS, Di GH, Jin W, Ou ZL, Shen ZZ, Shao ZM. · Breast Cancer Institute, Cancer Hospital, Department of Oncology, Shanghai Medical College, Institutes of Biomedical Science, Fudan University, Shanghai, 200032, People's Republic of China. · Breast Cancer Res. · Pubmed #17980029 links to  free full text

Abstract: INTRODUCTION: The molecular mechanisms involved in breast cancer metastasis still remain unclear to date. In our previous study, differential expression of peroxiredoxin 6 was found between the highly metastatic MDA-MB-435HM cells and their parental counterparts, MDA-MB-435 cells. In this study, we investigated the effects of peroxiredoxin 6 on the proliferation and metastatic potential of human breast cancer cells and their potential mechanism. METHODS: Expression of peroxiredoxin 6 in the highly metastatic MDA-MB-231HM cells was investigated by RT-PCR, real-time PCR and western blot. A recombinant expression plasmid of the human peroxiredoxin 6 gene was constructed and transfected into MDA-MB-231 and MDA-MB-435 cells. The effects of peroxiredoxin 6 on the proliferation and invasion of MDA-MB-231 and MDA-MB-435 cells were investigated by the Cell Counting Kit-8 method, colony-formation assay, adhesion assay, flow cytometry and invasion assay in vitro. miRNA was used to downregulate the expression of peroxiredoxin 6. Genes related to the invasion and metastasis of cancer were determined by RT-PCR, real-time PCR and western blot. The tumorigenicity and spontaneously metastatic capability regulated by peroxiredoxin 6 were determined using an orthotopic xenograft tumor model in athymic mice. RESULTS: Overexpression of peroxiredoxin 6 in MDA-MB-231HM cells compared with their parental counterparts was confirmed. Upregulation of peroxiredoxin 6 enhanced the in vitro proliferation and invasion of breast cancer cells. The enhancement was associated with decreasing levels of tissue inhibitor of matrix metalloproteinase (TIMP)-2 and increasing levels of the urokinase-type plasminogen activator receptor (uPAR), Ets-1 (E26 transformation-specific-1), matrix metalloproteinase (MMP)-9 and RhoC (ras homolog gene family, member C) expression. The results were further demonstrated by RNA interference experiments in vitro. In an in vivo study, we also demonstrated that peroxiredoxin 6-transfected breast cancer cells grew much faster and had more pulmonary metastases than control cells. By contrast, peroxiredoxin 6 knockdown breast cancer cells grew more slowly and had fewer pulmonary metastases. Effects similar to those of peroxiredoxin 6 on the uPAR, Ets-1, MMP-9, RhoC and TIMP-2 expression observed in in vitro studies were found in the in vivo study. CONCLUSION: Overexpression of peroxiredoxin 6 leads to a more invasive phenotype and metastatic potential in human breast cancer, at least in part, through regulation of the levels of uPAR, Ets-1, MMP-9, RhoC and TIMP-2 expression.

Chang XZ, Li DQ, Hou YF, Wu J, Lu JS, Di GH, Jin W, Ou ZL, Shen ZZ, Shao ZM. · Department of Oncology, Breast Cancer Institute, Cancer Hospital, Shanghai Medical College, Institutes of Biomedical Science, Fudan University, Shanghai, 200032, P.R. China. · Breast Cancer Res Treat. · Pubmed #17929166 No free full text.

Abstract: A novel highly metastatic MDA-MB-231HM cells, derived from MDA-MB-231, was established in our institute. RT-PCR, real-time PCR and Western blot showed that AF1Q gene was differentially expressed between highly metastatic MDA-MB-231HM cells and its parental MDA-MB-231 cells. However, its molecular mechanisms in breast cancer metastasis remain to be characterized. To investigate the effects of AF1Q on the progression of human breast cancer cells, in the present study, recombinant expression plasmid vectors of the human AF1Q gene was transfected into MDA-MB-231 cells. We demonstrated that AF1Q overexpression enhanced the in vitro proliferation and invasive potential of breast cancer cells. Focused microarray analyses showed that 22 genes were differentially expressed between AF1Q transfected cells and its parental counterparts. Integrin alpha3, accompanied by up-regulation of Ets-1 and MMP-2, significantly enhanced the in vitro invasive potential of human breast cancer cells mediated by AF1Q. Estrogen-responsive ring finger protein gene (EFP), also played a role in the enhancement of in vitro proliferation of human breast cancer cells mediated by AF1Q, accompanied by down-regulation of 14-3-3delta. The association was ERalpha independent. These results were further demonstrated by RNA interference (RNAi) experiment in vitro. In in vivo study, we also demonstrated that AF1Q transfected breast cancer cells grew much faster and had more pulmonary metastases than vector-transfected or its parental counterparts. On the contrary, AF1Q knockdown cells grew slower and had less pulmonary metastasis. Similar effects of AF1Q on integrin alpha3, Ets-1, MMP-2, EFP, and 14-3-3delta expression observed in vitro studies were also found in the in vivo study. Taken together, these results provide functional evidences that overexpression of AF1Q leads to a more progression in human breast cancer, at least in part, through regulating the integrin alpha3, Ets-1, MMP-2, EFP, and 14-3-3delta expression.

Li WF, Hu Z, Liu XY, Zhang B, Cao MZ, Wang YS, Zhao L, Liu YB, Yuan WT, Shen ZZ, Huang W, Shao ZM. · Breast Cancer Institute, Cancer Hospital/Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 PR China. · Zhonghua Yi Xue Yi Chuan Xue Za Zhi. · Pubmed #17922413 No free full text.

Abstract: OBJECTIVE: To investigate the role of disease associated germ line mutations in BRCA1 gene among Chinese early-onset breast cancer patients. METHODS: A total of 188 early-onset breast cancer patients, who were diagnosed with breast cancer before 41-year-old, were enrolled from four breast cancer clinical centers in China. Thirty-nine of them (20.7%) also had family history of breast/ovarian cancer. DNA extracted from lymphocytes was amplified by polymerase chain reaction (PCR) for the entire exons and the splicing sites of BRCA1. Twenty-two of the patients were screened by single strand conformation polymorphism (SSCP), and the other 166 of them were screened by denaturing high performance liquid chromatography (DHPLC). The abnormal fragments recognized were ascertained by DNA direct sequencing. For those samples with the same recurrent mutation, five BRCA1-linked markers (D17S855, D17S1322, D17S1323, D17S1326 and D17S1327) were used for the allelotype analysis. RESULTS: Twelve disease-associated mutations were identified in 15 (8.0%) patients, among which BRCA1 1100delAT and 5589del8 were identified in 3 and 2 patients respectively. Nine (23.1%) of them were identified in those with breast/ovarian cancer family history. The difference of BRCA1 mutation frequency between the patients with and without family history was statistically significant (P=0.001). Allelotype analysis showed the two BRCA1 5589del8 mutation carriers shared the same allelotype in all the 5 STR sites, and two of the three 1100delAT mutation carriers, who came from the northern China, also shared the same allelotype in all the 5 STR sites, which were different from those of the 5589del8 mutation carriers'. CONCLUSION: This is a relatively very large scale multi-hospital-based study of BRCA1 mutations in Chinese early-onset breast cancer patients up to now. It seems reasonable to give genetic consultations and genetic test of BRCA1 gene to early-onset breast cancer patients in China, especially for those with breast/ovarian cancer family history. The two recurrent mutations might be founder mutations of Chinese population. It might be cost-effective to analyze these two mutations before whole gene analysis.

Li WF, Hu Z, Rao NY, Song CG, Zhang B, Cao MZ, Su FX, Wang YS, He PQ, Di GH, Shen KW, Wu J, Lu JS, Luo JM, Liu XY, Zhou J, Wang L, Zhao L, Liu YB, Yuan WT, Yang L, Shen ZZ, Huang W, Shao ZM. · Department of Oncology, Breast Cancer Institute, Cancer Hospital/Cancer Institute, Institutes of Biomedical Science, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, PR China. · Breast Cancer Res Treat. · Pubmed #17851763 No free full text.

Abstract: To have an overview of the role of BRCA1 and BRCA2 genes among Chinese high-risk breast cancer patients, we analyzed 489 such high-risk breast cancer patients from four breast disease clinical centers in China, by using PCR-DHPLC or SSCP-DNA sequencing analysis. Allelotype analysis was done at five short tandem repeat (STR) markers in or adjacent to BRCA1 on the recurrent mutation carriers. For those analyzed both genes, 8.7% of early-onset breast cancer cases and 12.9% of familial breast cancer cases had a BRCA1 or BRCA2 mutation, as compared with the 26.1% of cases with both early-onset breast cancer and affected relatives. For those reporting malignancy family history other than breast/ovarian cancer, the prevalence of BRCA1/2 mutation is about 20.5%, and it was significantly higher than the patients only with family history of breast/ovarian cancer (P = 0.02). The family history of ovarian cancer (26.7% vs. 11.9%) and stomach cancer (23.8% vs. 11.8%) doubled the incidence of BRCA1/2, but the difference did not reach the statistical significance. Two recurrent mutations in BRCA1, 1100delAT and 5589del8, were identified. The recurrent mutations account for 34.8% BRCA1 mutations in our series. Similar allelotypes were detected in most STR status for those harboring the same mutations. The BRCA1 associated tumors were more likely to exhibit a high tumor grade, negative C-erbB-2/neu status and triple negative (ER, PgR and C-erbB-2/neu negative) status (P < 0.05). We recommended the BRCA1 and BRCA2 genetic analysis could be done for high-risk breast cancer patient in Chinese population, especially for those with both early-onset breast cancer and affected relatives. There may be some degree of shared ancestry for the two recurrent BRCA1 mutations in Chinese.

Hu Z, Li WF, Liu XY, Zhang B, Cao MZ, Wang YS, Zhao L, Song CG, Lu JS, Wu J, Di GH, Shen KW, Han QX, Shen ZZ, Huang W, Shao ZM. · Breast Cancer Institute, Cancer Hospital/Cancer Institute, Fudan University, Shanghai, 200032 P. R. China. · Zhonghua Yi Xue Yi Chuan Xue Za Zhi. · Pubmed #17680524 No free full text.

Abstract: OBJECTIVE: To study the "hot spot" of BRCA1/2 gene mutations in Chinese mainland breast cancer population. METHODS: The known BRCA1/2 gene mutations in author's previous studies were reanalyzed by denaturing high performance liquid chromatography and DNA sequencing method in 177 patients with early onset breast cancer or affected relatives and 426 sporadic breast cancer patients from four breast cancer centers in China. RESULTS: Three cases were found with BRCA1 5589del8 mutation out of 247 hereditary-predisposing breast cancer patients (70 patients in previous study and 177 patients in current study) and 2 cases with BRCA1 5589del8 mutation out of 426 sporadic breast cancer patients. They had similar even same haplotype. CONCLUSION: BRCA1 5589del8 mutation is likely to be the "founder mutation" in Chinese population, but it should be confirmed by further studies.

Di GH, Wu J, Yu KD, Lu JS, Shen KW, Shen ZZ, Shao ZM. · Department of Breast Surgery, Cancer Hospital, China. · Zhonghua Zhong Liu Za Zhi. · Pubmed #17575698 No free full text.

Abstract: OBJECTIVE: To evaluate the available surgical treatment modalities so as to explore the optimal strategy of managing early breast cancer. METHODS: The clinical data of 2173 consecutive early-stage breast cancer patients treated by surgery treatments were retrospectively reviewed in order to clarify the indications and contraindications of different modalities. Therapeutic outcome of different surgical treatment modes were compared in terms of recurrence-free survival ( RFS) , disease-free survival ( DFS) , overall survival (OS). The cosmetic results of breast conservation and reconstruction were also evaluated . RESULTS: The median age of these patients was 51 years ranging from 18 to 91. Of 2173 patients, 547 had stage 0- I lesions and 1626 stage II , and 1155 (53. 2% ) premenopausal. The proportion of patients who received radical surgery, breast conservation and reconstruction after mastectomy was 83. 6% (1817/2173), 10. 5% (229/2173) and 2. 5% (55/2173) , respectively. Younger and premenopausal patients prefer conservative and reconstructive surgeries, which are reasonable for stage 0-I and non-invasive breast cancer patients. Conservative surgery was not suitable for Paget's disease of breast (P = 0. 004) , mastectomy followed by reconstruction in this type of cancer was up to 38. 5%. The recurrence and metastasis rate of conservation or mastectomy were similar with a comparable 3-year RFS of 97. 4% and 95. 4% , respectively; there were also no significant differences in RFS(P =0. 2435) , DFS( P =0. 1395) and OS(P =0. 9406) after having been followed for 3 to 64 months. Similarly, immediate reconstruction did not show any negative effects with only 1 recurrence and 1 metastasis. Aesthetic outcomes were assessed as excellent or good in 90. 0% of breast conservation surgery, and the acceptability of reconstruction was 94. 5%. CONCLUSION: Breast conserving surgery not only has comparable survival as mastectomy, but also has better cosmetic outcomes. Immediate breast reconstruction can be a suitable option without compromising survival. It is very important in the management for early breast cancer by selecting the most suitable surgery mode for every individual patient not only to cure her disease but also to satisfy the patient psychologically. Conservation should be preferred prior to reconstruction whenever possible.