Guanglun Yang

Chongqing Medical University, Ch’ung-ch’ing-shih, Chongqing Shi, China

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Publications (5)17.5 Total impact

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    ABSTRACT: Cancer associated fibroblasts (CAFs) are crucial co-mediators of breast cancer progression. Estrogen is the predominant driving force in the cyclic regulation of the mammary extracellular matrix, thus potentially impacting on the tumor-associated stroma. Recently, a third estrogen receptor, estrogen (G-protein coupled) receptor (GPER) was reported to be expressed in breast CAFs. In this study, GPER was detected by immunohistochemical analysis in stromal fibroblasts of 41.8% (59/141) of primary breast cancers. GPER expression in CAFs isolated from primary breast cancer was confirmed by immunostaining and RT-PCR analyses. Tamoxifen (TAM) in addition to 17-β-estradiol (E2) and the GPER agonist G1 activated GPER, resulting in transient increases in cell index, intracellular calcium and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Furthermore, TAM, E2 and G1 promoted CAFs proliferation and cell cycle progression, both of which were blocked by GPER interference, the selective GPER antagonist, G15, the epidermal growth factor receptor (EGFR) inhibitor, AG1478 and the ERK1/2 inhibitor, U0126. Importantly, TAM as well as G1 increased estradiol production by breast CAFs via GPER/EGFR/ERK signaling when the substrate of estradiol, testosterone, was added to the medium. GPER-induced aromatase up-regulation was probably responsible for this phenomenon since TAM and G1 induced CYP19A1 gene expression was reduced by GPER knockdown, G15, AG1478 and U0126. Accordingly, GPER-mediated CAF-dependent estrogenic effects on the tumor-associated stroma are conceivable, and CAF is likely to contribute to breast cancer progression, especially TAM-resistance, via a positive feedback loop involving GPER/EGFR/ERK signaling and estradiol production.
    Endocrine Related Cancer 01/2014; DOI:10.1530/ERC-13-0237 · 4.91 Impact Factor
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    ABSTRACT: Tamoxifen is widely used to treat hormone-dependent breast cancer, but its therapeutic benefit is limited by the development of drug resistance. Here, we investigated the role of estrogen G-protein coupled receptor 30 (GPR30) on Tamoxifen resistance in breast cancer. Primary tumors (PTs) of breast cancer and corresponding metastases (MTs) were used to evaluate the expression of GPR30 and epidermal growth factor receptor (EGFR) immunohistochemically. Tamoxifen-resistant (TAM-R) subclones derived from parent MCF-7 cells were used to investigate the role of GPR30 in the development of tamoxifen resistance, using MTT assay, western blot, RT-PCR, immunofluorescence, ELISA and flow cytometry. TAM-R xenografts were established to assess anti-tumor effects of combination therapy with GPR30 antagonist G15 plus 4-hydroxytamoxifen (Tam), using tumor volume measurement and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). In 53 human breast cancer specimens, GPR30 expression in MTs increased compared to matched PTs; in MTs, the expression patterns of GPR30 and EGFR were closely related. Compared to parent MCF-7 cells, TAM-R cells had greater growth responses to 17beta-estradiol (E2), GPR30 agonist G1 and Tam, and significantly higher activation of Mitogen-activated protein (MAP) kinases; but this increased activity was abolished by G15 or AG1478. In TAM-R cells, GPR30 cell-surface translocation facilitated crosstalk with EGFR, and reduced cAMP generation, attenuating inhibition of EGFR signaling. Combination therapy both promoted apoptosis in TAM-R cells and decreased drug-resistant tumor progression. Long-term endocrine treatment facilitates the translocation of GPR30 to cell surfaces, which interferes with the EGFR signaling pathway; GPR30 also attenuates the inhibition of MAP kinases. These factors contribute to tamoxifen resistance development in breast cancer. Combination therapy with GPR30 inhibitors and tamoxifen may provide a new therapeutic option for drug-resistant breast cancer.
    Breast cancer research: BCR 11/2013; 15(6):R114. DOI:10.1186/bcr3581 · 5.88 Impact Factor
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    ABSTRACT: Aberrant expression of c-Ski oncoprotein in some tumor cells has been shown to be associated with cancer development. However, the role of c-Ski in cancer-associated fibroblasts (CAFs) of tumor microenvironment has not been characterized. In the current study, we found that c-Ski is highly expressed in CAFs derived from breast carcinoma microenvironment and this CAF-associated c-Ski expression is associated with invasion and metastasis of human breast tumors. We showed that c-Ski overexpression in immortalized breast normal fibroblasts (NFs) induces conversion to breast CAFs by repressing p53 and thereby upregulating SDF-1 in NFs. SDF-1 treatment or p53 knockdown in NFs had similar effects on the activation of NFs as c-Ski overexpression. The c-Ski-activated CAFs show increased proliferation, migration, invasion and contraction compared with NFs. Furthermore, c-Ski-activated CAFs facilitated the migration and invasion of MDA-MB-231 breast cancer cells. Our data suggest that c-Ski is an important regulator in the activation of CAFs and may serve as a potential therapeutic target to block breast cancer progression.
    Molecular oncology 08/2013; DOI:10.1016/j.molonc.2013.08.007 · 5.94 Impact Factor
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    ABSTRACT: Intra-arterial infusion chemotherapy for locally advanced breast cancer (LABC) has been previously performed. However, the main complications of this type of chemotherapy remain to be clarified. In the present study, catheterization chemotherapy was carried out for 53 LABC cases (stage IIIa-IIIc) between May, 2006 and March, 2007. For IIIB and IIIC patients, the catheters were guided to the opening of the subclavian artery. For stage IIIa patients, the catheters were placed into the thoracic artery through a subcutaneous femoral artery puncture. One to four cycles of chemotherapy (mean, 1.6 cycles) were administered for the patients using taxotere, epidoxorubicin, 5-fluorouracil and/or cyclophosphamide. The interval time between the two cycles was 21 days. Seven cases were identified as complete response (CR, 13.2%), 41 cases were partial response (PR, 77.4%) with a rate of effectiveness of (CR + PR, 90.6%), 5 cases were stable disease (SD, 9.40%) and no case was progressive. Pain of the ipsilateral upper extremity was present in 7 cases. Two cases exhibited ipsilateral upper extremity atrophy following drug administration from the opening of the subclavian artery. One case experienced neck pain and headache, while in one case necrosis of local skin was evident. Hematological toxicity over grade 3 was observed in 6 cases (11.30%). Systemic toxicity was mild and did not affect the quality of life of the patients. Overall survival was identified as 18/51 (35.3%), and free-disease survival as 10/51 (19.6%). In conclusion, intra-arterial infusion chemotherapy is an effective local control treatment for LABC. The main complications are pain of the ipsilateral upper extremity and neck as well as headache. Severe complications are ipsilateral upper extremity atrophy and necrosis of local skin. During the treatment, controlling the pressure of the tourniquet and velocity of drug administration are crucial for reducing local complications.
    Molecular and Clinical Oncology 07/2013; 1(4):745-748. DOI:10.3892/mco.2013.129
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    ABSTRACT: In this study, the effects of pirrolidine dithiocarbamate (PDTC) plus leflunomide (Lef) and cyclosporine (CsA) on the NF-kappaB signaling pathway in mouse-to-rat cardiac xeno-transplantation models were investigated. NIH mice and Wistar rats served as donors and recipients respectively. Mouse-to-rat cardiac xenotransplantation was performed. The recipients were divided into 5 groups: group A (the control group), group B (PDTC group), group C (PDTC plus CsA group), group D (PDTC plus Lef group) and group E (PDTC plus Lef and CsA group). The expressions of IKKalpha/beta, NF-kappaB-P65, IkappaBalpha, ICAM-1 and NF-kappaB DNA binding activity in xenograft tissues were determined by immunohistochemistry and Western blot as well as electrophoretic mobility shift assay (EMSA). The median survival time of cardiac xenografts in the control group, PDTC group, PDTC plus CsA group, PDTC plus Lef group and PDTC plus Lef and CsA group was (2.17+/-0.41), (2.33+/-0.52), (4.67+/-1.21), (7.00+/-1.79) and (9.00+/-1.41) days respectively. The survival time of xenografts in the PDTC plus Lef and CsA group was significantly longer than that in other four groups (P<0.05 for all), that in the PDTC plus Lef group longer than that in the control group, PDTC group and PDTC plus CsA group (P<0.05 for all), that in PDTC plus CsA group longer than the control group and PDTC group (P<0.05 for all). The expressions of IKKalpha/beta, NF-kappaB-P65, IkappaBalpha and ICAM-1 and NF-kappaB DNA binding activity were notably increased in mouse-to-rat cardiac xenografts. The expressions were decreased in the control group, PDTC group, PDTC plus CsA group, PDTC plus Lef and PDTC plus Lef and CsA group in turn. It was concluded that PDTC plus Lef and CsA can significantly suppress the expressions of IKKalpha/beta, NF-kappaB-P65, IkappaBalpha, ICAM-1 and NF-kappaB DNA binding activity, thereby prolonging the survival of the cardiac xenografts.
    Journal of Huazhong University of Science and Technology 04/2009; 29(2):202-6. DOI:10.1007/s11596-009-0213-2 · 0.78 Impact Factor

Publication Stats

21 Citations
17.50 Total Impact Points


  • 2013
    • Chongqing Medical University
      Ch’ung-ch’ing-shih, Chongqing Shi, China
  • 2009
    • Chongqing University of Medical Science
      • First Affiliated Hospital
      Ch’ung-ch’ing-shih, Chongqing Shi, China