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Bombesin antagonists inhibit growth of MDA-MB-435 estrogen-independent breast cancers and decrease the expression of
Ana M Bajo1, Andrew V Schally, Magdalena Krupa
1Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center and Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Abstract:
Previous studies showed that antagonists of bombesin (BN)/gastrin-releasing peptide (GRP) inhibit the growth of various cancers by interfering with the growth-stimulatory effects of BN-like peptides and down-regulating epidermal growth factor receptors on tumors. Because the overexpression of the human epidermal growth factor receptor-2 (ErbB-2/HER-2/neu) oncogene plays a role in the progression of many breast cancers, we investigated whether BN/GRP antagonists can affect HER-2 in mammary tumors. Female nude mice bearing orthotopic xenografts of MDA-MB-435 human estrogen-independent breast cancers were treated daily with BN/GRP antagonists RC-3095 (20 microg) or RC-3940-II (10 microg) for 6 weeks. The expression of BN/GRP receptors on tumors was analyzed by reverse transcription-PCR and immunoblotting. We also evaluated whether the mRNA expression for the c-jun and c-fos oncogenes is affected by the therapy. Both BN/GRP antagonists significantly inhibited growth of MDA-MB-435 cancers; RC-3095 reduced tumor volume by 40% and RC-3940-II by 65%. The GRP receptors (subtype 1) were detected in MDA-MB-435 tumors, showing that they mediate the inhibitory effect of the antagonists. Tumor inhibition was associated with a substantial reduction in the expression of mRNA and protein levels of the ErbB/HER receptor family as well as with a decrease in the expression of c-jun and c-fos oncogenes. BN/GRP antagonists RC-3940-II and RC-3095 could be considered for endocrine therapy of estrogen-independent breast cancers that express members of the ErbB/HER receptor family and the c-jun and c-fos oncogenes.
Insights
Bombesin (BN)/gastrin-releasing peptide (GRP) antagonists significantly inhibited estrogen-independent breast cancer growth in mice. These antagonists reduced tumor volume by down-regulating HER-2, c-jun, and c-fos oncogenes.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Bombesin (BN)/gastrin-releasing peptide (GRP) antagonists inhibit cancer growth by blocking BN-like peptides and down-regulating epidermal growth factor receptors.
- Overexpression of human epidermal growth factor receptor-2 (HER-2) oncogene contributes to breast cancer progression.
Purpose of the Study:
- To investigate the effect of BN/GRP antagonists on HER-2 in mammary tumors.
- To evaluate the potential of BN/GRP antagonists as a therapeutic strategy for estrogen-independent breast cancers.
Main Methods:
- Female nude mice with orthotopic MDA-MB-435 human estrogen-independent breast cancer xenografts were treated with BN/GRP antagonists RC-3095 or RC-3940-II.
- Tumor growth, BN/GRP receptor expression, and mRNA/protein levels of HER-2, c-jun, and c-fos oncogenes were analyzed.
Main Results:
- Both BN/GRP antagonists significantly inhibited tumor growth, with RC-3095 reducing volume by 40% and RC-3940-II by 65%.
- Tumor inhibition correlated with reduced expression of HER-2, c-jun, and c-fos mRNA and protein.
- GRP receptors (subtype 1) were detected in tumors, mediating the antagonists' inhibitory effect.
Conclusions:
- BN/GRP antagonists RC-3940-II and RC-3095 demonstrate significant efficacy in inhibiting estrogen-independent breast cancer growth.
- These antagonists represent a potential therapeutic option for breast cancers overexpressing HER-2 and the c-jun/c-fos oncogenes.