Aiping Shi

Salidroside inhibits the growth of human breast cancer in vitro and in vivo

Salidroside has been identified as one of the most potent compounds isolated from the plant Rhodiola rosea, and was found to have several important biological properties, including antioxidant and anti-inflammatory activity; however, its anticancer effects are poorly understood. Thus, the present study focused on evaluating the effects of purified salidroside on the growth of human breast cancer in vitro and in vivo, and on further investigating its possible molecular mechanisms. The human breast cancer cell line, MCF-7, was incubated with various concentrations of salidroside, and cell proliferation, colony formation, cell cycle distribution, apoptosis, migration and invasion were assayed by several in vitro approaches. As a result, it was found that salidroside treatment significantly inhibited cell proliferation, colony formation, migration and invasion, as well as induced cell apoptosis and cell cycle arrest at the G0/G1 phase in vitro. In addition, we also evaluated the effect of salidroside on tumor growth in a nude mouse model, and found that salidroside treatment significantly suppressed tumor growth in vivo. We also further disclosed that salidroside treatment significantly inhibited the intracellular reactive oxygen species (ROS) formation and MAPK pathway activation, which may contribute to the inhibition of tumor growth of breast cancer and reduction of oxidative stress. In conclusion, these findings suggest that salidroside may be a promising candidate target for the prevention and treatment of human breast cancer.

The expression of aldehyde dehydrogenase 1 in invasive primary breast tumors and axillary lymph node metastases is associated with poor clinical prognosis.

The enzyme aldehyde dehydrogenase 1 (ALDH1) has been reported as a biomarker for identifying cancer stem cells. Previous studies have shown that ALDH1 expression in primary breast cancers was associated with poor clinical prognosis. In this study, we aimed to determine whether ALDH1 expression in axillary lymph node metastases (ALNM) of breast cancer patients was also associated with poor prognosis. Expression of ALDH1, ER, PgR, HER2 and KI-67 was examined in primary tumors and ALNM of 161 patients with invasive breast cancer. Survival analysis and multivariate analysis were used to determine the relationship between ALDH1 expression and clinical prognosis. Patients with positive ALDH1 expression in primary tumors and in ALNM had significantly shorter relapse-free survival (RFS) times and overall survival (OS) times compared to those whose tissues were ALDH1 negative. ALDH1-positivity in primary tumors was significant both in univariate and multivariate analyses of RFS and OS. ALDH1 expression in ALNM was significant in a univariate analysis of RFS and OS but not in a multivariate analysis of RFS and OS. We conclude that the expression of ALDH1 in primary breast tumors or ALNM may be one potential risk factor for poor, long-term outcomes.

Subcutaneous Nipple-Sparing Mastectomy and Immediate Breast Reconstruction.

Background: Without a doubt, nipple-sparing mastectomy affords a better cosmetic result than modified radical mastectomy. However, the surgical safety, radicality, complications, indications, and psychological benefits associated with this method are controversially discussed. Patients and Methods: We carried out a retrospective analysis of 35 patients (study group) who underwent nipple-sparing mastectomy between 2000 and 2008. Indications, incision selection, postoperative complications, recurrence, morbidity rate, and psychological status were recorded and assessed. Results: The survival outcome (5.7 vs. 6%; p = 0.35) and complication rate (5.7 vs. 19%; p = 0.062) of patients who underwent subcutaneous nipple-sparing mastectomy and immediate breast reconstruction with prosthesis were similar to those of patients who underwent modified radical mastectomy. Most patients in the study group were completely satisfied with the aesthetic results (immediately, p < 0.001; < 1 year, p < 0.001; > 1 year, p < 0.001), and no serious psychological disorders or stress were detected relative to patients with traditional mastectomy. Conclusion: Subcutaneous nipple-sparing mastectomy was beneficial and safe in this cohort of breast cancer patients. The approach is suitable for patients with isolated lesions located ≥ 2 cm from the nipple, as well as for patients with multiple lesions who are anxious about a good cosmetic appearance.

COX-2 silencing enhances tamoxifen antitumor activity in breast cancer in vivo and in vitro

Tamoxifen (Tam), a selective estrogen receptor modulator, is in wide clinical use for the treatment and prevention of breast cancer. However, extended TAM administration for breast cancer induces increased VEGF levels in patients, promoting new blood vessel formation and thereby limiting its efficacy and highlighting the need for improved therapeutic strategies. Cyclooxygenase-2 (COX-2) silencing via a replication-incompetent lentivirus (LV-COX-2) induce cancer apoptosis and suppresses VEGF gene expression. In this study, the effect of LV-COX-2 infection, either alone or in combination with TAM, was analyzed in a breast cell lines for suppressing VEGF expression and simultaneously reducing doses of TAM. Cell proliferation, apoptosis, angiogenesis, metastasis, cell cycle distribution, an receptor signaling were determined after LV-COX-2 combination with TAM treatment. In addition, tumor growth ability in nude mice was detected to define the combination treatment effect in tumorigenesis in vivo. It is found that LV-COX-2 combination with TAM treatment in breast cancer cell significantly suppressed the proliferation and metastasis, and induced tumor apoptosis in vitro, and tumor growth also was suppressed in vivo. In addition, we also found that LV-COX-2 combination with TAM treatment could inhibit angiogenesis and VEGF expression. Taken together, our experimental results indicate that LV-COX-2 combination with TAM has promising outcome in anti-metastatic and apoptotic studies. Furthermore, these results showed that LV-COX-2 combination with TAM is a potential drug candidate for treatment of breast tumors expressing high levels of VEGF.

Aldehyde dehydrogenase 1 (ALDH1) expression is associated with a poor prognosis of bladder cancer.

Aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, has been reported to be altered in human carcinogenesis. This study assessed the expression of ALDH1 protein in invasive vs. noninvasive bladder cancer tissues for association with clinicopathological factors and bladder cancer prognosis. Tissue samples were collected from 227 bladder cancer patients, including 118 with noninvasive and 109 with invasive bladder cancer for immunostaining of ALDH1 expression. ALDH1 expression in tumor tissues was significantly greater than that in adjacent normal tissues. ALDH1 protein was highly expressed in 29.07% (66/227) of bladder tumor tissues (i.e., 24.58% of noninvasive bladder cancer tissues vs. 33.94% of invasive bladder cancer tissues). In patients with noninvasive bladder cancer, ALDH1 protein expression was significantly associated with an advanced tumor grade and frequent tumor recurrence (P≤0.05). In patients with invasive bladder cancer, ALDH1 protein expression was significantly associated with an advanced tumor grade, stage, as well as lymph node and distant metastases (P≤0.05). After adjusting for the confounding factors, ALDH1 protein expression was significantly associated with relapse-free survival in noninvasive bladder cancer patients [HR (95% CI)=4.45 (1.32-15.04); P=0.027] and overall survival in invasive bladder cancer patients [HR (5% CI)=2.86 (1.72-8.83); P=0.020]. These data indicate that ALDH1 expression plays an important role in bladder cancer development and prognosis. Further validation of our results is warranted in a larger sample cohort, and further investigation of ALDH1 signaling and function will increase our understanding of ALDH1 in bladder cancer progression.

Clinical Features and Prognosis of a Unilateral Fibroadenoma of the Breast in a 16-Month-Old Female

Fibroadenoma of the breast is a common benign disease, occurring mainly in females younger than 30 years of age. Infant fibroadenoma is extremely rare. Here, we report on a 16-month-old female with a 6 month history of unilateral progressive breast enlargement. Upon clinical evaluation, a palpable mass was observed in the upper and outer quarter of the right breast. The single tumor was solid and well circumscribed. Various clinical examinations were performed, including determination of hormone levels, ultrasound, mammography, magnetic resonance imaging, as well as the collection of a fine needle aspiration. The results showed that the sex hormones were present at normal levels. The size of the tumor was approximately 3 × 3 × 3 cm. Enlarged lymph nodes were not detected in the axillary region or any other regions. The tumor was removed surgically and fibroadenoma was diagnosed post-operatively. The patient was followed up for 38 months and no tumor recurrence was observed.

Nogo-B receptor increases the resistance of estrogen receptor positive breast cancer to paclitaxel

Intrinsic or acquired chemoresistance is a hurdle in oncology. Only 7%-16% of estrogen receptor α (ERα) positive breast cancer cases achieve a pathological complete response (pCR) after neo-adjuvant chemotherapy. Nogo-B receptor (NgBR) is a cell surface receptor that binds farnesylated Ras and promotes Ras translocation to the plasma membrane. Here, we demonstrate NgBR as a potential therapeutic target for ERα positive breast cancer patients to attenuate paclitaxel resistance. NgBR knockdown enhanced paclitaxel-induced cell apoptosis by modulating expression of p53 and survivin in ERα positive breast cancer cells via NgBR-mediated PI3K/Akt and MAPK/ERK signaling pathways. NgBR knockdown attenuated either 17β-estradiol or epidermal growth factor stimulated phosphorylation of ERα at Serine 118 residue. The ChIP-PCR assay further demonstrated that NgBR knockdown decreased ERα binding to the estrogen response element (ERE) of the ERα target gene and increased the binding of p53 to the promoter region of survivin to attenuate survivin transcription. In summary, our data suggest that NgBR expression is essential to promoting ERα positive breast cancer cell resistance to paclitaxel. Findings from this study implicate a novel therapeutic target for treating ERα positive breast cancer in neo-adjuvant/adjuvant chemotherapy.

Nogo-B receptor increases the resistance to tamoxifen in estrogen receptor-positive breast cancer cells

BackgroundsTamoxifen is typically used to treat patients with estrogen receptor alpha (ERα)-positive breast cancer. However, 30% of these patients gain acquired resistance to tamoxifen during or after tamoxifen treatment. As a Ras modulator, Nogo-B receptor (NgBR) is required for tumorigenesis through the signaling crosstalk with epidermal growth factor (EGF) receptor (EGFR)-mediated pathways. NgBR is highly expressed in many types of cancer cells and regulates the sensitivity of hepatocellular carcinoma to chemotherapy. In this study, we found the expression of NgBR is increased in tamoxifen-resistant ERα-positive breast cancer cells.MethodsTamoxifen-resistant ERα-positive MCF-7 and T47D breast cancer cell lines were established by culturing with gradually increased concentration of 4-hydroxytamoxifen (4-OHT). The effects of NgBR on tamoxifen resistance was determined by depleting NgBR in these cell lines using previously validated small interfering RNA (siRNA). The effects of 4-OHT on cell viability and apoptosis were determined using well-accepted methods such as clonogenic survival assay and Annexin V/propidium iodide staining. The alteration of EGF-stimulated signaling and gene expression was determined by western blot analysis and real-time PCR, respectively.ResultsNgBR knockdown with siRNA attenuates EGF-induced phosphorylation of ERα and restores the sensitivity to tamoxifen in ERα-positive breast cancer cells. Mechanistically, our data demonstrated that NgBR knockdown increases the protein levels of p53 and decreases survivin, which is an apoptosis inhibitor.ConclusionsThese results suggested that NgBR is a potential therapeutic target for increasing the sensitivity of ERα-positive breast cancer to tamoxifen.

Prognostic value of routine laboratory variables in prediction of breast cancer recurrence

The prognostic value of routine laboratory variables in breast cancer has been largely overlooked. Based on laboratory tests commonly performed in clinical practice, we aimed to develop a new model to predict disease free survival (DFS) after surgical removal of primary breast cancer. In a cohort of 1,596 breast cancer patients, we analyzed the associations of 33 laboratory variables with patient DFS. Based on 3 significant laboratory variables (hemoglobin, alkaline phosphatase, and international normalized ratio), together with important demographic and clinical variables, we developed a prognostic model, achieving the area under the curve of 0.79. We categorized patients into 3 risk groups according to the prognostic index developed from the final model. Compared with the patients in the low-risk group, those in the medium- and high-risk group had a significantly increased risk of recurrence with a hazard ratio (HR) of 1.75 (95% confidence interval [CI] 1.30–2.38) and 4.66 (95% CI 3.54–6.14), respectively. The results from the training set were validated in the testing set. Overall, our prognostic model incorporating readily available routine laboratory tests is powerful in identifying breast cancer patients who are at high risk of recurrence. Further study is warranted to validate its clinical application.

Expression of Stem Cells Marker ALDH1 in Premalignant Lesions, Cancer,Benign Hyperplasia and Normal Duct of Human Breast

Purpose: To study the differences of ALDH1 expression in Invasive Ductal Carcinoma (IDC), Atypical Ductal Hyperplasia (ADH), Usual Ductal Hyperplasia (UDH) and normal ducts and their clinical significance. Materials and Methods: Immunohistochemistry method was used to detect the expression of ALDH1 in 160 cases of IDC, 50 cases of ADH, 20 cases of UDH and 22 normal duct cases. Results: ALDH1 was expressed in a few cells in most samples except in a few cases of ADH, UDH and normal ducts, in which ALDH1 expression showed extensive distribution. The positive rate of ALDH1 expression in luminal epithelial cytoplasm of IDC, ADH and UDH was 35%, 64% and 80%, while in myoepithelial cells and stroma of IDC, ADH and UDH was 40%, 52% and 70%. ALDH1 expression in luminal epithelial cytoplasm of IDC has correlation with OS and RFS of the breast cancer patients (P 0.05). The chi-square test of ALDH1 expression in luminal epithelial cytoplasm of three kinds of tissues has shown statistical significance (P 0.05). Conclusion: The positive expression of ALDH1 may play a role during the evolution of disease from ADH to breast cancer, as ALDH1 has a predicted value in outcome of breast cancer.