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Loss of B-cell translocation gene 2 expression in estrogen receptor-positive breast cancer predicts tamoxifen resistance.

Takahashi M, Hayashida T, Okazaki H, Miyao K, Jinno H, Kitagawa Y - Cancer Sci. (2014)

Bottom Line: To determine if BTG2 expression modifies tamoxifen efficacy, a cohort of 60 patients treated with adjuvant tamoxifen monotherapy was analyzed.We found that increased BTG2 expression showed better clinical survival and was the only independent prognostic factor for disease-free survival (hazard ratio, 0.691; 95% confidence interval, 0.495-0.963; P = 0.029).These studies demonstrate that BTG2 is a significant factor in tamoxifen response, acting through modification of AKT activation in ER-positive/HER2-negative breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

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(a) Immunohistochemistry of epiregulin (EREG) in tumor samples from (i,ii) tetracycline (Tet)( −) and (iii,iv) Tet(+); original magnification: (i,iii) ×100; (ii,iv) ×200. (b) Crosstalk between estrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER2)-AKT pathway was modified by B-cell translocation gene 2 (BTG2) expression. BTG2 was induced for 48 h by 1 μg/mL tetracycline treatment of MCF7/tet-BTG2 cells. These cells were serum starved for 6 h and then treated either with or without 1 μM tamoxifen (Tam) for 24 h. Western blotting of total cell lysates was used to monitor the expression of BTG2 and the kinetics of HER2, IGF1R and AKT phosphorylation.
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fig05: (a) Immunohistochemistry of epiregulin (EREG) in tumor samples from (i,ii) tetracycline (Tet)( −) and (iii,iv) Tet(+); original magnification: (i,iii) ×100; (ii,iv) ×200. (b) Crosstalk between estrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER2)-AKT pathway was modified by B-cell translocation gene 2 (BTG2) expression. BTG2 was induced for 48 h by 1 μg/mL tetracycline treatment of MCF7/tet-BTG2 cells. These cells were serum starved for 6 h and then treated either with or without 1 μM tamoxifen (Tam) for 24 h. Western blotting of total cell lysates was used to monitor the expression of BTG2 and the kinetics of HER2, IGF1R and AKT phosphorylation.

Mentions: Clinical and laboratory evidence supports an essential role for crosstalk between the ER and HER2 signaling pathways in resistance to hormone therapies.13,14,22 As has been shown previously, both estrogen and tamoxifen can activate the HER2 signaling pathway and stimulate tumor growth via non-genomic ER activity.13,23 In addition, suppression of BTG2 strongly induces the activation of HER2 and HER3 phosphorylation, which is reduced by the restoration of BTG2 expression due to neuregulin-1, and epiregulin (EREG) was induced via transcript stabilization on knockdown of BTG2.11 In the immunohistochemical staining of tumors consisted of MCF7-RASV12/tet-BTG2 cells, EREG expression was observed under the condition of loss of BTG2. In contrast, EREG expression was reduced with BTG2 overexpression, which is consistent with the results of a previous study11 (Fig.5a).


Loss of B-cell translocation gene 2 expression in estrogen receptor-positive breast cancer predicts tamoxifen resistance.

Takahashi M, Hayashida T, Okazaki H, Miyao K, Jinno H, Kitagawa Y - Cancer Sci. (2014)

(a) Immunohistochemistry of epiregulin (EREG) in tumor samples from (i,ii) tetracycline (Tet)( −) and (iii,iv) Tet(+); original magnification: (i,iii) ×100; (ii,iv) ×200. (b) Crosstalk between estrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER2)-AKT pathway was modified by B-cell translocation gene 2 (BTG2) expression. BTG2 was induced for 48 h by 1 μg/mL tetracycline treatment of MCF7/tet-BTG2 cells. These cells were serum starved for 6 h and then treated either with or without 1 μM tamoxifen (Tam) for 24 h. Western blotting of total cell lysates was used to monitor the expression of BTG2 and the kinetics of HER2, IGF1R and AKT phosphorylation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317889&req=5

fig05: (a) Immunohistochemistry of epiregulin (EREG) in tumor samples from (i,ii) tetracycline (Tet)( −) and (iii,iv) Tet(+); original magnification: (i,iii) ×100; (ii,iv) ×200. (b) Crosstalk between estrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER2)-AKT pathway was modified by B-cell translocation gene 2 (BTG2) expression. BTG2 was induced for 48 h by 1 μg/mL tetracycline treatment of MCF7/tet-BTG2 cells. These cells were serum starved for 6 h and then treated either with or without 1 μM tamoxifen (Tam) for 24 h. Western blotting of total cell lysates was used to monitor the expression of BTG2 and the kinetics of HER2, IGF1R and AKT phosphorylation.
Mentions: Clinical and laboratory evidence supports an essential role for crosstalk between the ER and HER2 signaling pathways in resistance to hormone therapies.13,14,22 As has been shown previously, both estrogen and tamoxifen can activate the HER2 signaling pathway and stimulate tumor growth via non-genomic ER activity.13,23 In addition, suppression of BTG2 strongly induces the activation of HER2 and HER3 phosphorylation, which is reduced by the restoration of BTG2 expression due to neuregulin-1, and epiregulin (EREG) was induced via transcript stabilization on knockdown of BTG2.11 In the immunohistochemical staining of tumors consisted of MCF7-RASV12/tet-BTG2 cells, EREG expression was observed under the condition of loss of BTG2. In contrast, EREG expression was reduced with BTG2 overexpression, which is consistent with the results of a previous study11 (Fig.5a).

Bottom Line: To determine if BTG2 expression modifies tamoxifen efficacy, a cohort of 60 patients treated with adjuvant tamoxifen monotherapy was analyzed.We found that increased BTG2 expression showed better clinical survival and was the only independent prognostic factor for disease-free survival (hazard ratio, 0.691; 95% confidence interval, 0.495-0.963; P = 0.029).These studies demonstrate that BTG2 is a significant factor in tamoxifen response, acting through modification of AKT activation in ER-positive/HER2-negative breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

Show MeSH
Related in: MedlinePlus