The growth hormone receptor antagonist pegvisomant blocks both mammary gland development and MCF-7 breast cancer xenograft growth.
Mammary gland development is dependent upon the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis, this same axis has also been implicated in breast cancer progression. In this study we investigated the effect of a GH antagonist, pegvisomant (Somavert, Pfizer), on normal mammary gland development and breast cancer xenograft growth. Intraperitoneal administration of pegvisomant resulted in a 60% suppression of hepatic IGF-I mRNA levels and upto a 70-80% reduction of serum IGF-I levels. Pegvisomant administration to virgin female mice caused a significant delay of mammary ductal outgrowth that was associated with a decrease in the number of terminal end buds and reduced branching and complexity of the gland. This effect of pegvisomant was mediated by a complete inhibition of both GH and IGF-IR-mediated signaling within the gland. In breast cancer xenograft studies, pegvisomant caused shrinkage of MCF-7 xenografts, with an initial 30% reduction in tumor volume, which was associated with a 2-fold reduction in proliferation and a 2-fold induction of apoptosis. Long-term growth inhibition of MCF-7 xenografts was noted. In contrast, pegvisomant had no effect on MDA-231 or MDA-435 xenografts, consistent with primary growth of these xenografts being unresponsive to IGF-I both in vitro and in vivo. In MCF-7 xenografts that regressed, pegvisomant had only minor effects upon GHR and IGF-IR signaling. This data supports previous studies indicating a role for GH/IGF in mammary gland development, and suggests that pegvisomant maybe useful for the prevention and/or treatment of estrogen receptor positive breast cancer.
Divisova
Jana
J
Department of Medicine, Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
Kuiatse
Isere
I
Lazard
ZaWaunyka
Z
Weiss
Heidi
H
Vreeland
Franzanne
F
Hadsell
Darryl L
DL
Schiff
Rachel
R
Osborne
C Kent
CK
Lee
Adrian V
AV
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D019382:Human Growth Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D042361:Mammary Glands, Human / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D011960:Receptors, Estrogen; D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; C406545:pegvisomant