Functional roles of BCAR3 in the signaling pathways of insulin leading to DNA synthesis, membrane ruffling and GLUT4 translocation

Oh, Myounghak; Yi, Sun‐Ju; Kim, Hye Sung; Kim, Jihyun; Jeong, Young-Hwa; Agthoven, Ton van; Jhun, Byung Hak

doi:10.1016/j.bbrc.2013.10.161

Cited by 10 publications

(14 citation statements)

References 26 publications

(40 reference statements)

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“…However, and in contrast to the function of BCL2 , estrogen independence mediated by BCAR3 is transmitted through mechanisms distinct from the ER‐signaling pathway (Dorssers et al., 2005). BCAR3 , as part of an intracellular signal transduction pathway that causes estrogen‐independent proliferation in human breast cancer cells, promotes cell motility and adhesion, processes required for cells to become metastatic (Oh et al., 2013; Wilson et al., 2013). Additional studies from our group demonstrated that high levels of BCAR3 were associated with clinical benefit and prolonged PFS (van Agthoven et al., 2009a), which has now been validated in a larger cohort for both the adjuvant (Danish cohort) and the recurrent settings (Dutch cohorts, which also include the original cohort used to identify BCAR3 as a predictive marker).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the ability of adjuvant tamoxifen‐benefit gene signatures to predict outcome of hormone‐naive estrogen receptor‐positive breast cancer patients treated with tamoxifen in the advanced setting

et al. 2014

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To identify molecular markers indicative of response to tamoxifen and easily implemented in the routine setting, we recently reported three gene signatures that could stratify post-menopausal tamoxifen-treated, estrogen receptor-positive (ER+) patients according to outcome in the adjuvant setting. Here, we evaluated the predictive potential of the total of 14 genes included in the 3 gene signatures using 2 hormone-naïve Dutch ER+ cohorts of a total of 285 recurrent breast cancer patients treated with first-line tamoxifen. mRNA levels were measured by reverse transcriptase quantitative PCR (RT-qPCR) and the length of progression-free survival (PFS) was used as the primary endpoint. A Mann-Whitney U test was used to select for differentially expressed genes between tumors of patients who showed or did not show progressive disease within 6 months after start of tamoxifen treatment. Cox univariate and multivariate regression analysis for PFS were used to further assess their (independent) predictive potential. Five (BCAR3, BCL2, ESR1, IGF1R, and NCOA1) of the 14 genes analyzed showed significantly higher mRNA levels in tumors of patients who showed no disease progression within 6 months. Only BCAR3, BCL2 and NAT1 were significantly associated with a favorable PFS in multivariate analysis that included the traditional predictive factors: age, dominant relapse site, disease-free interval, ER and progesterone receptor (PGR), and adjuvant chemotherapy. This study shows that BCAR3, BCL2 and NAT1 in particular exhibit predictive promise regarding the efficacy of tamoxifen treatment in recurrent disease, in addition to the previously shown favorable outcome in the adjuvant setting.

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Section: Discussionmentioning

confidence: 99%

Evaluation of the ability of adjuvant tamoxifen‐benefit gene signatures to predict outcome of hormone‐naive estrogen receptor‐positive breast cancer patients treated with tamoxifen in the advanced setting

et al. 2014

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“…Antibodies to c-Jun, were obtained from BD Biosciences (San Jose, CA with media including serum for 24 hr using DMRIE-C reagent (Invitrogen, Carlsbad, CA) as described previously [17]. To measure c-jun mRNA level, real-time fluorescence quantitative PCR was used as described previously [17] …”

Section: Methodsmentioning

confidence: 99%

“…We previously reported that BCAR3 directly interacts with tyrosine-phosphorylated EGF receptors through the SH2 domain of BCAR3 and regulates DNA synthesis induced by EGF and insulin [16,17]. In addition, BCAR3 directly inter-acts with a downstream p130Cas, also known as BCAR1, through C-terminal GEF domain and acts as an adaptor molecule regulating cell transformation and cancer progression [26].…”

Section: Bcar3 Is a Member Of The Novel Sh2-containing Proteinmentioning

confidence: 99%

“…We previously reported single cell microinjection using a semiautomatic Eppendorf microinjection system [16,17].…”

Section: Microinjection Of Antibodies Sirna and Expression Vectorsmentioning

confidence: 99%

“…MCF-12A cells were transfected with either empty LNCX or BCAR3 expression LNCX vector [17]. Transfected cells were selected using G418 (100 μg/ml) and BCAR3 ex- …”

Section: Preparation Of Bcar3-overexpressing Cells and Cell Proliferamentioning

confidence: 99%

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Induction of c-Jun Expression by Breast Cancer Anti-estrogen Resistance-3 (BCAR3) in Human Breast MCF-12A Cells

Oh¹,

Kim²,

Jhun³

2016

Journal of Life Science

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Anti-estrogen drugs such as tamoxifen have been used for treating patients with ER-positive, early breast cancer. However, resistance to anti-estrogen treatment is inevitable in most patients. Breast cancer anti-estrogen resistance-3 (BCAR3) has been identified as the protein responsible for the induction of tamoxifen resistance in estrogen-dependent human breast cancer. We have previously reported that BCAR3 regulates the cell cycle progression and the signaling pathway of EGF and insulin leading to DNA synthesis. In this study, we investigated the functional role of BCAR3 in regulating c-Jun transcription in non-tumorigenic human breast epithelial MCF-12A cells. A transient transfection of BCAR3 increased both the mRNA and protein of c-Jun expression, and stable expression of BCAR3 increased c-Jun protein expression. The overexpression of BCAR3 directly activated the promoter of c-jun, AP-1, and SRE but not that of NF-κB. Furthermore, single-cell microinjection of BCAR3 expression plasmid in the cell cycle-arrested MCF-12A cells induced c-Jun protein expression, and co-injection of dominant negative mutants of Ras, Rac, and Rho suppressed the transcriptional activity of c-Jun in the presence of BCAR3. Furthermore, stable expression of BCAR3 increased the proliferation of MCF-12A cells. The microinjection of inhibitory materials such as anti-BCAR3 antibody and siRNA BCAR3 inhibited EGF-induced c-Jun expression but did not affect IGF-1 induced upregulation of c-Jun. Taken together, we propose that BCAR3 plays a crucial role in c-Jun protein expression and cell proliferation and that small GTPases (e.g., Ras, Rac, and Rho) are required for the BCAR3-mediated activation of c-Jun expression.

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Somatic environment and germinal differentiation in antral follicle: The effect of FSH withdrawal and basal LH on oocyte competence acquisition in cattle

Sirard

2016

Theriogenology

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Functional roles of BCAR3 in the signaling pathways of insulin leading to DNA synthesis, membrane ruffling and GLUT4 translocation

Cited by 10 publications

References 26 publications

Evaluation of the ability of adjuvant tamoxifen‐benefit gene signatures to predict outcome of hormone‐naive estrogen receptor‐positive breast cancer patients treated with tamoxifen in the advanced setting

Evaluation of the ability of adjuvant tamoxifen‐benefit gene signatures to predict outcome of hormone‐naive estrogen receptor‐positive breast cancer patients treated with tamoxifen in the advanced setting

Induction of c-Jun Expression by Breast Cancer Anti-estrogen Resistance-3 (BCAR3) in Human Breast MCF-12A Cells

Somatic environment and germinal differentiation in antral follicle: The effect of FSH withdrawal and basal LH on oocyte competence acquisition in cattle

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