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Zhi-Ming Shao

Publications and source records attributed to Zhi-Ming Shao.

At least 19 recordsLinked to original sources
PubMed2026

Integrated analysis reveals the impact of obesity on triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous breast cancer subtype with limited therapeutic options. While the prevalence of overweight/obese (OW/OB) women continues to rise, the impact of obesity on molecular features of TNBC remains incompletely understood. We investigated clinicopathological and molecular data (including genomic, transcriptomic, proteomic and metabolomic profiling) using our original multi-omics database of TNBC (N = 465) for associations with patient body mass index (BMI). Multi-omics profiling revealed that OW/OB patients exhibited worse survival as well as elevated inflammation of tumor microenvironment, higher expression of immune checkpoints, and dysregulated lipid metabolism. Our in vivo experiments demonstrated that tumors in obese mice displayed faster growth rates, a higher proportion of PD-1+CD8+ T cells and enhanced responsiveness to anti-PD-1 treatment. In addition, we analyzed data from four independent clinical trials and discovered that OW/OB patients demonstrated higher pathological complete response rates and longer progression-free survival following anti-PD-1-based immunotherapy. In conclusion, our study systematically revealed that obesity is associated with coordinated immune-metabolic remodeling in TNBC, characterized by checkpoint enrichment and lipid dysregulation, which may help explain the enhanced anti-PD-1 responsiveness and should be taken into account in the field of precision medicine.

Immunity↗
PubMed2026

Spatial proteogenomic profiling uncovers sensitization strategies for antibody-drug conjugate in HER2-positive breast cancer.

Antibody-drug conjugates (ADCs) have transformed the treatment of HER2-positive breast cancer, yet resistance remains poorly understood. Using imaging mass cytometry, we profiled 157 regions of interest comprising 912,360 single cells from 47 HER2-positive/hormone receptor-negative breast cancers treated with SHR-A1811 in the FASCINATE-N trial. Spatial proteomic analyses identified two determinants of ADC response: elevated tumor-cell H3K27ac expression was associated with improved ADC efficacy, whereas collagen-positive fibroblasts mediated resistance. Combining ADC with the histone deacetylase inhibitor chidamide or the collagen-modulating agent losartan produced synergistic antitumor effects in preclinical models. These biomarkers and therapeutic vulnerabilities were independently validated in patients with advanced HER2-positive disease receiving trastuzumab deruxtecan. Moreover, based on these spatial features, we developed a clinically applicable ADC barrier prediction model that can be implemented using multiplex immunofluorescence. Taken together, our findings reveal actionable spatial determinants of ADC efficacy and suggest potential combination therapeutic strategies.

Humans↗
PubMed2026

Age-related genomic characterization and therapeutic targets in Chinese breast cancer: insights from prospective targeted sequencing and clinical data analysis.

BACKGROUND: In China, breast cancer occurs at a much younger age and has a higher recurrence and mortality rate. However, with changes in lifestyle, there has been a trend towards an older age of breast cancer incidence in Chinese women. There is a paucity of large-scale next-generation sequencing cohorts for the analysis of genomic characterization in these populations and the identification of potential therapeutic targets. METHODS: To address this gap, we performed prospective targeted sequencing of tumor and blood samples from Chinese patients and collected detailed clinical information. We then categorized patients into two groups based on age (<&#x2009;40&#xa0;years, n&#x2009;=&#x2009;637;&#x2009;&#x2265;&#x2009;40&#xa0;years, n&#x2009;=&#x2009;3442) and proceeded to provide comprehensive descriptions of somatic and germline mutations in both groups. RESULTS: The somatic mutation analysis revealed that PIK3CA, FOXA1, and TBX3 mutations were more prevalent in elderly patients. By leveraging the aforementioned mutational characteristics, we employed our institution's FUTURE-SUPER clinical trial, an umbrella study targeting metastatic breast cancer, to confirm the potential benefits of PI3K-AKT-mTOR pathway inhibitors among elderly patients with breast cancer. Furthermore, TP53 and ERBB2 were more likely to be co-mutated in young women. Patients with TP53 and ERBB2 co-mutation tend to have a poorer prognosis, but through investigation of the SPARK cohort, patients carrying the TP53 and ERBB2 co-mutation are more likely to benefit from immune checkpoint inhibitor combination with tyrosine kinase inhibitor therapy. In our study, we observed a higher frequency of mutations in the DNA homology-dependent recombination pathway in young patients with breast cancer, which was associated with an elevated Ki67 index. Additionally, we confirmed a significant prevalence of germline breast cancer susceptibility gene 1 (gBRCA1) mutations in young patients, whereas germline checkpoint kinase 2 (gCHEK2) mutations are more common in elderly patients. CONCLUSIONS: Our study, which makes use of the largest Chinese breast cancer sequencing cohort, sought to characterize the age-related genomic profile of breast cancer patients and identify novel therapeutic opportunities for individuals with breast cancer.

Adult↗
PubMed2006

Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival.

Autophagy is a cellular response to adverse environment and stress, but its significance in cell survival is not always clear. Here we show that autophagy could be induced in the mammalian cells by chemicals, such as A23187, tunicamycin, thapsigargin, and brefeldin A, that cause endoplasmic reticulum stress. Endoplasmic reticulum stress-induced autophagy is important for clearing polyubiquitinated protein aggregates and for reducing cellular vacuolization in HCT116 colon cancer cells and DU145 prostate cancer cells, thus mitigating endoplasmic reticulum stress and protecting against cell death. In contrast, autophagy induced by the same chemicals does not confer protection in a normal human colon cell line and in the non-transformed murine embryonic fibroblasts but rather contributes to cell death. Thus the impact of autophagy on cell survival during endoplasmic reticulum stress is likely contingent on the status of cells, which could be explored for tumor-specific therapy.

Animals↗
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

Cyclin e expression and prognosis in breast cancer patients: a meta-analysis of published studies.

In vitro studies showed that cyclin E can accelerate the cell cycle by shorten the G1/S phase transition. Therefore, varieties of studies have investigated the relationship between cyclin E and survival in breast cancer patients. However, the results differed widely between studies. We reviewed the published studies and performed a meta-analysis, which including 12 independent studies and 2,534 patients. The combined HR estimate for relapse-free survival (RFS) was 2.32 (95% CI, 1.25-4.30) and 1.72 (95% CI, 0.95-3.10) in univariate and multivariate analysis, respectively. In addition, the combined HR estimate for overall survival (OS) and breast cancer specific survival (BCSS) was 2.98 (95% CI, 1.85-4.78) and 2.86 (95% CI, 1.85-4.41) in univariate and multivariate analysis, respectively. In conclusion, the high level of cyclin E appears to be an independent prognostic factor to OS/BCSS of breast cancer patients but not to RFS.

Breast Neoplasms↗
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↗
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

Identification of a novel endothelial-derived gene EG-1.

The identification of novel endothelial-derived genes is important in the study of angiogenesis, and may have potential uses in cancer diagnosis and treatment. We performed SSH (suppression subtractive hybridization) on control HUVECs (human umbilical vein endothelial cells) versus HUVECs exposed to tumor-conditioned media. We found that a novel cDNA (GenBank Accession No. AF358829) is differentially expressed in endothelial cells on Northern analysis, and named it endothelial-derived gene-1 (EG-1). This gene product is predicted to encode a 178-aa, 19.5-kDa protein, and is localized to chromosome 4. It has some homology to a mouse cDNA (94%) and a Drosophila cDNA (31%). On Northern analysis, endothelial cells express two EG-1 RNA species (1.2 and 2.4 kb). The expression of either transcripts is upregulated by endothelial cells when exposed to tumor conditioned media. This phenomenon is observed only under sparse conditions (50% confluency). Transcripts are present abundantly in highly vascular tissues such as placenta, testis, and liver. Interestingly, both Northern analysis and in situ hybridization studies show that this gene is expressed in other cell types as well, predominantly the epithelial type. Breast cancer, prostate cancer, and colon cancer cells show elevated expression of the higher 2.4-kb RNA form. Our data suggest that EG-1 is associated with a stimulated state in endothelial and epithelial cells, and may have a role in tumor angiogenesis.

Amino Acid Sequence↗
PubMed2002

Angiogenic factors and bladder cancer.

Angiogenesis is required for the growth as well as expansion of a solid tumor. It has been reported that tumor angiogenesis may be triggered after an increase in the level of angiogenic factors and a concomitant decrease in the level of angiogenic inhibitors. Of all potential pro-angiogenic mediators of bladder cancer, VEGF and bFGF appear to be most relevant in terms of physiology. To date, it appears that the angiogenic factors and inhibitors may play an important role in the diagnosis and prognosis of bladder cancer.

Angiogenesis Inducing Agents↗
PubMed2002

Green tea inhibits vascular endothelial growth factor (VEGF) induction in human breast cancer cells.

Investigators have shown that green tea and its main catechin epigallocatechin-3 gallate (EGCG) may decrease the risk of cancer. Our previous study showed that green tea extract (GTE) as well as its individual catechin components inhibited MDA-MB231 breast cancer cell and human umbilical vein endothelial cell (HUVEC) proliferation. Further, GTE suppressed breast cancer xenograft size and decreased the tumor vessel density in vivo. In the current study, we investigated the effect of GTE on the major angiogenic factor vascular endothelial growth factor (VEGF) in an in vitro experiment. GTE or EGCG (40 mg/L) significantly decreased the levels of the VEGF peptide secreted into conditioned media. This occurred in both HUVEC and human breast cancer cells and the effect was dose dependent. Furthermore, GTE and EGCG decreased the RNA levels of VEGF in MDA-MB231 cells. This inhibition occurred at the transcriptional regulation level and was accompanied by a significant decrease in VEGF promoter activity. We also showed that GTE decreased c-fos and c-jun RNA transcripts, suggesting that activator protein (AP)-1-responsive regions present in the human VEGF promoter may be involved in the inhibitory effect of GTE. Furthermore, GTE suppressed the expression of protein kinase C, another VEGF transcription modulator, in breast cancer cells. Inhibition of VEGF transcription appeared to be one of the molecular mechanism(s) involved in the antiangiogenic effects of green tea, which may contribute to its potential use for breast cancer treatment and/or prevention.

Beverages↗