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Elafin, an inhibitor of elastase, is a prognostic indicator in breast cancer.

Hunt KK, Wingate H, Yokota T, Liu Y, Mills GB, Zhang F, Fang B, Su CH, Zhang M, Yi M, Keyomarsi K - Breast Cancer Res. (2013)

Bottom Line: Control-treated xenografts generated a tumor burden that necessitated sacrifice within one month of initial treatment, whereas xenograft-bearing mice treated with Ad-Elafin were alive at eight months with marked reduction in tumor growth.Elastase inhibition mimicked these results, showing decreased tumor cell growth in vitro and in vivo.Low expression of elafin gene correlated with significantly reduced time to relapse, and when combined with high expression of elastase gene was associated with decreased survival in breast cancer patients.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Elafin is an elastase-specific inhibitor with increased transcription in normal mammary epithelial cells compared to mammary carcinoma cells. In this report, we test the hypothesis that inhibition of elastase, through induction of elafin, leads to inhibition of human breast cancer cell viability and, therefore, predicts survival in breast cancer patients.

Methods: Panels of normal and immortalized breast epithelial cells, along with breast carcinoma cells, were used to examine the impact of adenoviral-mediated elafin expression or shRNA-mediated inhibition of elastase on the growth of cells and xenografts in nude mice. To determine the prognostic significance of decreased elafin in patients with invasive breast cancer, previously published gene array datasets were interrogated.

Results: Elafin expression had no effect on non-tumorigenic cells but resulted in marked inhibition of cell growth in breast cancer cell lines. Control-treated xenografts generated a tumor burden that necessitated sacrifice within one month of initial treatment, whereas xenograft-bearing mice treated with Ad-Elafin were alive at eight months with marked reduction in tumor growth. Elastase inhibition mimicked these results, showing decreased tumor cell growth in vitro and in vivo. Low expression of elafin gene correlated with significantly reduced time to relapse, and when combined with high expression of elastase gene was associated with decreased survival in breast cancer patients.

Conclusion: Our data suggest that elafin plays a direct role in the suppression of tumors through inhibition of elastase and thus serves as a prognostic indicator for breast cancer patients.

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Related in: MedlinePlus

Elafin treatment of mice with breast cancer xenografts leads to increased survival. Nude mice with established MDA-MB-468 xenografts were treated with Ad-Elafin (n = 6), PBS (n = 4) or Ad-Luc (n = 4). A) Tumor volume was measured and recorded every other day. Mice were sacrificed when tumors were greater than 1.5 cm in diameter, and B) survival was recorded. The results show the average of two replicate experiments.
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Figure 5: Elafin treatment of mice with breast cancer xenografts leads to increased survival. Nude mice with established MDA-MB-468 xenografts were treated with Ad-Elafin (n = 6), PBS (n = 4) or Ad-Luc (n = 4). A) Tumor volume was measured and recorded every other day. Mice were sacrificed when tumors were greater than 1.5 cm in diameter, and B) survival was recorded. The results show the average of two replicate experiments.

Mentions: Elastase inhibition by shRNA provides a means to decrease the tumor burden in a xenograft model (Figure 2C, D). To further assess if overexpression of elafin and down-regulation of elastase have similar physiological endpoints, we next investigated the effect of elafin expression on tumor progression in an in vivo model. MDA-MB-468 cells were injected into the mammary fat pad of nude mice and were then treated with Ad-Luc, PBS or Ad-Elafin and the tumor burden was monitored over the duration of the study. Tumors in the mice treated with Ad-Luc or PBS continued to grow, requiring sacrifice within 45 days. However, there was an immediate cessation in tumor growth in the mice treated with Ad-Elafin (P < .0001, Figure 5A). All of the mice treated with Ad-Elafin remained alive for at least 45 days after initial treatment (Figure 5B). Ten of the 12 mice treated with Ad-Elafin experienced tumor growth necessitating sacrifice between Days 50 and 100. At eight months after initial treatment, one mouse treated with Ad-Elafin had experienced a decrease in tumor size to less than 30 mm3, and one had experienced complete resolution of the tumor. Elafin treatment resulted in significantly improved event-free survival compared with PBS or Ad-Luc treatment (P < 0.001, Figure 5B).


Elafin, an inhibitor of elastase, is a prognostic indicator in breast cancer.

Hunt KK, Wingate H, Yokota T, Liu Y, Mills GB, Zhang F, Fang B, Su CH, Zhang M, Yi M, Keyomarsi K - Breast Cancer Res. (2013)

Elafin treatment of mice with breast cancer xenografts leads to increased survival. Nude mice with established MDA-MB-468 xenografts were treated with Ad-Elafin (n = 6), PBS (n = 4) or Ad-Luc (n = 4). A) Tumor volume was measured and recorded every other day. Mice were sacrificed when tumors were greater than 1.5 cm in diameter, and B) survival was recorded. The results show the average of two replicate experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672770&req=5

Figure 5: Elafin treatment of mice with breast cancer xenografts leads to increased survival. Nude mice with established MDA-MB-468 xenografts were treated with Ad-Elafin (n = 6), PBS (n = 4) or Ad-Luc (n = 4). A) Tumor volume was measured and recorded every other day. Mice were sacrificed when tumors were greater than 1.5 cm in diameter, and B) survival was recorded. The results show the average of two replicate experiments.
Mentions: Elastase inhibition by shRNA provides a means to decrease the tumor burden in a xenograft model (Figure 2C, D). To further assess if overexpression of elafin and down-regulation of elastase have similar physiological endpoints, we next investigated the effect of elafin expression on tumor progression in an in vivo model. MDA-MB-468 cells were injected into the mammary fat pad of nude mice and were then treated with Ad-Luc, PBS or Ad-Elafin and the tumor burden was monitored over the duration of the study. Tumors in the mice treated with Ad-Luc or PBS continued to grow, requiring sacrifice within 45 days. However, there was an immediate cessation in tumor growth in the mice treated with Ad-Elafin (P < .0001, Figure 5A). All of the mice treated with Ad-Elafin remained alive for at least 45 days after initial treatment (Figure 5B). Ten of the 12 mice treated with Ad-Elafin experienced tumor growth necessitating sacrifice between Days 50 and 100. At eight months after initial treatment, one mouse treated with Ad-Elafin had experienced a decrease in tumor size to less than 30 mm3, and one had experienced complete resolution of the tumor. Elafin treatment resulted in significantly improved event-free survival compared with PBS or Ad-Luc treatment (P < 0.001, Figure 5B).

Bottom Line: Control-treated xenografts generated a tumor burden that necessitated sacrifice within one month of initial treatment, whereas xenograft-bearing mice treated with Ad-Elafin were alive at eight months with marked reduction in tumor growth.Elastase inhibition mimicked these results, showing decreased tumor cell growth in vitro and in vivo.Low expression of elafin gene correlated with significantly reduced time to relapse, and when combined with high expression of elastase gene was associated with decreased survival in breast cancer patients.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Elafin is an elastase-specific inhibitor with increased transcription in normal mammary epithelial cells compared to mammary carcinoma cells. In this report, we test the hypothesis that inhibition of elastase, through induction of elafin, leads to inhibition of human breast cancer cell viability and, therefore, predicts survival in breast cancer patients.

Methods: Panels of normal and immortalized breast epithelial cells, along with breast carcinoma cells, were used to examine the impact of adenoviral-mediated elafin expression or shRNA-mediated inhibition of elastase on the growth of cells and xenografts in nude mice. To determine the prognostic significance of decreased elafin in patients with invasive breast cancer, previously published gene array datasets were interrogated.

Results: Elafin expression had no effect on non-tumorigenic cells but resulted in marked inhibition of cell growth in breast cancer cell lines. Control-treated xenografts generated a tumor burden that necessitated sacrifice within one month of initial treatment, whereas xenograft-bearing mice treated with Ad-Elafin were alive at eight months with marked reduction in tumor growth. Elastase inhibition mimicked these results, showing decreased tumor cell growth in vitro and in vivo. Low expression of elafin gene correlated with significantly reduced time to relapse, and when combined with high expression of elastase gene was associated with decreased survival in breast cancer patients.

Conclusion: Our data suggest that elafin plays a direct role in the suppression of tumors through inhibition of elastase and thus serves as a prognostic indicator for breast cancer patients.

Show MeSH
Related in: MedlinePlus