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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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Tamoxifen treatment effectively inhibits tumor progression with B-cell translocation gene 2 (BTG2) expression. (a) MCF7-RASV12/tet-BTG2 cells were inoculated into the mammary fat pad of 6-week-old female BALB/c nude mice. After the tumors grew to a volume of more than 125 mm3, mice harboring these tumors were administered water containing tetracycline (Tet) and/or tamoxifen (Tam) pellets for 3 weeks. Tumor growth ratios were measured in all four groups ([×]: Tet(−)Tam(−), n = 11; [▴]: Tet(+)Tam(−), n = 10; [•]: Tet(−)Tam(+), n = 11; [▀]: Tet(+)Tam(+), n = 8). Data are shown as averages ± SE. Tumor growth ratio was significantly suppressed with the concomitant administration of tetracycline and tamoxifen in comparison with the animals treated with tamoxifen alone (P = 0.044, Tet[−]Tam[+] vs Tet[+]Tam[+]; Student's t-test). (b) Tumors were harvested at 21 days after treatment to be weighed. Tumor weight was also significantly suppressed with the concomitant administration of tetracycline and tamoxifen in comparison with the animals treated with tamoxifen alone (P = 0.034, Tet[-]Tam[+] vs Tet[+]Tam[+]; Student's t-test). (c) Immunohistochemistry of Ki-67 in tumor samples from Tet(−)Tam(+) and Tet(+)Tam(+) mice. (d) The number of portions stained by Ki-67. The Ki-67 ratios were significantly different between Tet(−)Tam(+) and Tet(+)Tam(+) mice (P = 0.039; Student's t-test). The average number of stains was counted by studying three portions in each slide.
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fig04: Tamoxifen treatment effectively inhibits tumor progression with B-cell translocation gene 2 (BTG2) expression. (a) MCF7-RASV12/tet-BTG2 cells were inoculated into the mammary fat pad of 6-week-old female BALB/c nude mice. After the tumors grew to a volume of more than 125 mm3, mice harboring these tumors were administered water containing tetracycline (Tet) and/or tamoxifen (Tam) pellets for 3 weeks. Tumor growth ratios were measured in all four groups ([×]: Tet(−)Tam(−), n = 11; [▴]: Tet(+)Tam(−), n = 10; [•]: Tet(−)Tam(+), n = 11; [▀]: Tet(+)Tam(+), n = 8). Data are shown as averages ± SE. Tumor growth ratio was significantly suppressed with the concomitant administration of tetracycline and tamoxifen in comparison with the animals treated with tamoxifen alone (P = 0.044, Tet[−]Tam[+] vs Tet[+]Tam[+]; Student's t-test). (b) Tumors were harvested at 21 days after treatment to be weighed. Tumor weight was also significantly suppressed with the concomitant administration of tetracycline and tamoxifen in comparison with the animals treated with tamoxifen alone (P = 0.034, Tet[-]Tam[+] vs Tet[+]Tam[+]; Student's t-test). (c) Immunohistochemistry of Ki-67 in tumor samples from Tet(−)Tam(+) and Tet(+)Tam(+) mice. (d) The number of portions stained by Ki-67. The Ki-67 ratios were significantly different between Tet(−)Tam(+) and Tet(+)Tam(+) mice (P = 0.039; Student's t-test). The average number of stains was counted by studying three portions in each slide.

Mentions: After 21 days of treatment there was no significant difference in tumor volumes between treated and untreated tumors in animals bearing control tumors (n = 11) or mice treated with tetracycline alone (n = 10), suggesting that BTG2 expression did not affect tumor growth in this xenograft model (Fig4a). Tamoxifen treatment alone, without tetracycline (n = 10), significantly decreased the tumor growth ratio compared with the negative control (P = 0.009). Remarkably, the tumor growth ratio was strongly suppressed, to a statistically significant level, with concomitant administration of tetracycline and tamoxifen (n = 8) in comparison with tamoxifen monotherapy (P = 0.044; Fig4a). Correspondingly, tamoxifen treatment in the context of BTG2 expression significantly reduced the tumor weight compared with tamoxifen treatment alone (P = 0.034; Fig4b). Concomitant administration of tamoxifen and tetracycline led to decreased Ki-67 expression compared with the control group (P = 0.009) or the group treated with tamoxifen alone (P = 0.039; Fig.4c,d).


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)

Tamoxifen treatment effectively inhibits tumor progression with B-cell translocation gene 2 (BTG2) expression. (a) MCF7-RASV12/tet-BTG2 cells were inoculated into the mammary fat pad of 6-week-old female BALB/c nude mice. After the tumors grew to a volume of more than 125 mm3, mice harboring these tumors were administered water containing tetracycline (Tet) and/or tamoxifen (Tam) pellets for 3 weeks. Tumor growth ratios were measured in all four groups ([×]: Tet(−)Tam(−), n = 11; [▴]: Tet(+)Tam(−), n = 10; [•]: Tet(−)Tam(+), n = 11; [▀]: Tet(+)Tam(+), n = 8). Data are shown as averages ± SE. Tumor growth ratio was significantly suppressed with the concomitant administration of tetracycline and tamoxifen in comparison with the animals treated with tamoxifen alone (P = 0.044, Tet[−]Tam[+] vs Tet[+]Tam[+]; Student's t-test). (b) Tumors were harvested at 21 days after treatment to be weighed. Tumor weight was also significantly suppressed with the concomitant administration of tetracycline and tamoxifen in comparison with the animals treated with tamoxifen alone (P = 0.034, Tet[-]Tam[+] vs Tet[+]Tam[+]; Student's t-test). (c) Immunohistochemistry of Ki-67 in tumor samples from Tet(−)Tam(+) and Tet(+)Tam(+) mice. (d) The number of portions stained by Ki-67. The Ki-67 ratios were significantly different between Tet(−)Tam(+) and Tet(+)Tam(+) mice (P = 0.039; Student's t-test). The average number of stains was counted by studying three portions in each slide.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig04: Tamoxifen treatment effectively inhibits tumor progression with B-cell translocation gene 2 (BTG2) expression. (a) MCF7-RASV12/tet-BTG2 cells were inoculated into the mammary fat pad of 6-week-old female BALB/c nude mice. After the tumors grew to a volume of more than 125 mm3, mice harboring these tumors were administered water containing tetracycline (Tet) and/or tamoxifen (Tam) pellets for 3 weeks. Tumor growth ratios were measured in all four groups ([×]: Tet(−)Tam(−), n = 11; [▴]: Tet(+)Tam(−), n = 10; [•]: Tet(−)Tam(+), n = 11; [▀]: Tet(+)Tam(+), n = 8). Data are shown as averages ± SE. Tumor growth ratio was significantly suppressed with the concomitant administration of tetracycline and tamoxifen in comparison with the animals treated with tamoxifen alone (P = 0.044, Tet[−]Tam[+] vs Tet[+]Tam[+]; Student's t-test). (b) Tumors were harvested at 21 days after treatment to be weighed. Tumor weight was also significantly suppressed with the concomitant administration of tetracycline and tamoxifen in comparison with the animals treated with tamoxifen alone (P = 0.034, Tet[-]Tam[+] vs Tet[+]Tam[+]; Student's t-test). (c) Immunohistochemistry of Ki-67 in tumor samples from Tet(−)Tam(+) and Tet(+)Tam(+) mice. (d) The number of portions stained by Ki-67. The Ki-67 ratios were significantly different between Tet(−)Tam(+) and Tet(+)Tam(+) mice (P = 0.039; Student's t-test). The average number of stains was counted by studying three portions in each slide.
Mentions: After 21 days of treatment there was no significant difference in tumor volumes between treated and untreated tumors in animals bearing control tumors (n = 11) or mice treated with tetracycline alone (n = 10), suggesting that BTG2 expression did not affect tumor growth in this xenograft model (Fig4a). Tamoxifen treatment alone, without tetracycline (n = 10), significantly decreased the tumor growth ratio compared with the negative control (P = 0.009). Remarkably, the tumor growth ratio was strongly suppressed, to a statistically significant level, with concomitant administration of tetracycline and tamoxifen (n = 8) in comparison with tamoxifen monotherapy (P = 0.044; Fig4a). Correspondingly, tamoxifen treatment in the context of BTG2 expression significantly reduced the tumor weight compared with tamoxifen treatment alone (P = 0.034; Fig4b). Concomitant administration of tamoxifen and tetracycline led to decreased Ki-67 expression compared with the control group (P = 0.009) or the group treated with tamoxifen alone (P = 0.039; Fig.4c,d).

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