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Relevance of BCAR4 in tamoxifen resistance and tumour aggressiveness of human breast cancer.

Godinho MF, Sieuwerts AM, Look MP, Meijer D, Foekens JA, Dorssers LC, van Agthoven T - Br. J. Cancer (2010)

Bottom Line: In BCAR4-expressing cells, phosphorylation of v-erb-b2 erythroblastic leukaemia viral oncogene homolog (ERBB)2, ERBB3, and their downstream mediators extracellular signal-regulated kinase 1/2 and v-akt murine thymoma viral oncogene homolog (AKT) 1/2, was increased.Selective knockdown of ERBB2 or ERBB3 inhibited proliferation, confirming their role in BCAR4-induced tamoxifen resistance.Our cell model suggests that BCAR4-positive breast tumours are driven by ERBB2/ERBB3 signalling.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus MC-University Medical Center Rotterdam, Rotterdam, 3000 CA, The Netherlands.

ABSTRACT

Background: Breast cancer anti-oestrogen resistance 4 (BCAR4) was identified in a search for genes involved in anti-oestrogen resistance in breast cancer. We explored whether BCAR4 is predictive for tamoxifen resistance and prognostic for tumour aggressiveness, and studied its function.

Methods: BCAR4 mRNA levels were measured in primary breast tumours, and evaluated for association with progression-free survival (PFS) and clinical benefit in patients with oestrogen receptor (ERα)-positive tumours receiving tamoxifen as first-line monotherapy for advanced disease. In a separate cohort of patients with lymph node-negative, ERα-positive cancer, and not receiving systemic adjuvant therapy, BCAR4 levels were evaluated for association with distant metastasis-free survival (MFS). The function of BCAR4 was studied with immunoblotting and RNA interference in a cell model.

Results: Multivariate analyses established high BCAR4 mRNA levels as an independent predictive factor for poor PFS after start of tamoxifen therapy for recurrent disease. High BCAR4 mRNA levels were associated with poor MFS and overall survival, reflecting tumour aggressiveness. In BCAR4-expressing cells, phosphorylation of v-erb-b2 erythroblastic leukaemia viral oncogene homolog (ERBB)2, ERBB3, and their downstream mediators extracellular signal-regulated kinase 1/2 and v-akt murine thymoma viral oncogene homolog (AKT) 1/2, was increased. Selective knockdown of ERBB2 or ERBB3 inhibited proliferation, confirming their role in BCAR4-induced tamoxifen resistance.

Conclusion: BCAR4 may have clinical relevance for tumour aggressiveness and tamoxifen resistance. Our cell model suggests that BCAR4-positive breast tumours are driven by ERBB2/ERBB3 signalling. Patients with such tumours may benefit from ERBB-targeted therapy.

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Related in: MedlinePlus

Progression-free survival of 280 patients with advanced disease treated with first-line tamoxifen monotherapy. Kaplan–Meier curves for PFS for subgroups of patients as a function of BCAR4 mRNA status. Patients at risk at 12-month intervals are indicated.
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fig1: Progression-free survival of 280 patients with advanced disease treated with first-line tamoxifen monotherapy. Kaplan–Meier curves for PFS for subgroups of patients as a function of BCAR4 mRNA status. Patients at risk at 12-month intervals are indicated.

Mentions: Univariate Cox regression analysis revealed that the presence of BCAR4 mRNA was significantly associated with shorter PFS (positive vs negative HR=1.45, P=0.007, Table 1). High levels were significantly associated with shorter PFS (high vs negative HR=1.70, P=0.003), whereas low levels were not informative. The Kaplan–Meier curves for PFS in these subgroups show rapid progression of the disease in patients with high levels of BCAR4 (Figure 1).


Relevance of BCAR4 in tamoxifen resistance and tumour aggressiveness of human breast cancer.

Godinho MF, Sieuwerts AM, Look MP, Meijer D, Foekens JA, Dorssers LC, van Agthoven T - Br. J. Cancer (2010)

Progression-free survival of 280 patients with advanced disease treated with first-line tamoxifen monotherapy. Kaplan–Meier curves for PFS for subgroups of patients as a function of BCAR4 mRNA status. Patients at risk at 12-month intervals are indicated.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2967058&req=5

fig1: Progression-free survival of 280 patients with advanced disease treated with first-line tamoxifen monotherapy. Kaplan–Meier curves for PFS for subgroups of patients as a function of BCAR4 mRNA status. Patients at risk at 12-month intervals are indicated.
Mentions: Univariate Cox regression analysis revealed that the presence of BCAR4 mRNA was significantly associated with shorter PFS (positive vs negative HR=1.45, P=0.007, Table 1). High levels were significantly associated with shorter PFS (high vs negative HR=1.70, P=0.003), whereas low levels were not informative. The Kaplan–Meier curves for PFS in these subgroups show rapid progression of the disease in patients with high levels of BCAR4 (Figure 1).

Bottom Line: In BCAR4-expressing cells, phosphorylation of v-erb-b2 erythroblastic leukaemia viral oncogene homolog (ERBB)2, ERBB3, and their downstream mediators extracellular signal-regulated kinase 1/2 and v-akt murine thymoma viral oncogene homolog (AKT) 1/2, was increased.Selective knockdown of ERBB2 or ERBB3 inhibited proliferation, confirming their role in BCAR4-induced tamoxifen resistance.Our cell model suggests that BCAR4-positive breast tumours are driven by ERBB2/ERBB3 signalling.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus MC-University Medical Center Rotterdam, Rotterdam, 3000 CA, The Netherlands.

ABSTRACT

Background: Breast cancer anti-oestrogen resistance 4 (BCAR4) was identified in a search for genes involved in anti-oestrogen resistance in breast cancer. We explored whether BCAR4 is predictive for tamoxifen resistance and prognostic for tumour aggressiveness, and studied its function.

Methods: BCAR4 mRNA levels were measured in primary breast tumours, and evaluated for association with progression-free survival (PFS) and clinical benefit in patients with oestrogen receptor (ERα)-positive tumours receiving tamoxifen as first-line monotherapy for advanced disease. In a separate cohort of patients with lymph node-negative, ERα-positive cancer, and not receiving systemic adjuvant therapy, BCAR4 levels were evaluated for association with distant metastasis-free survival (MFS). The function of BCAR4 was studied with immunoblotting and RNA interference in a cell model.

Results: Multivariate analyses established high BCAR4 mRNA levels as an independent predictive factor for poor PFS after start of tamoxifen therapy for recurrent disease. High BCAR4 mRNA levels were associated with poor MFS and overall survival, reflecting tumour aggressiveness. In BCAR4-expressing cells, phosphorylation of v-erb-b2 erythroblastic leukaemia viral oncogene homolog (ERBB)2, ERBB3, and their downstream mediators extracellular signal-regulated kinase 1/2 and v-akt murine thymoma viral oncogene homolog (AKT) 1/2, was increased. Selective knockdown of ERBB2 or ERBB3 inhibited proliferation, confirming their role in BCAR4-induced tamoxifen resistance.

Conclusion: BCAR4 may have clinical relevance for tumour aggressiveness and tamoxifen resistance. Our cell model suggests that BCAR4-positive breast tumours are driven by ERBB2/ERBB3 signalling. Patients with such tumours may benefit from ERBB-targeted therapy.

Show MeSH
Related in: MedlinePlus