new work on how to block IGFR1 induced breast cancer growth

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Breast Cancer Research and Treatment
Publisher: Springer Netherlands
ISSN: 0167-6806 (Paper) 1573-7217 (Online)
DOI: 10.1007/s10549-006-9168-1
Issue: Online First
The growth hormone receptor antagonist pegvisomant blocks both mammary gland development and MCF-7 breast cancer xenograft growth
Jana Divisova1, Isere Kuiatse1, ZaWaunyka Lazard1, Heidi Weiss1, Franzanne Vreeland2, Darryl L. Hadsell3, Rachel Schiff1, C. Kent Osborne1 and Adrian V. Lee1, 4

(1) Departments of Medicine and Molecular and Cellular Biology, Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
(2) Pfizer Global Research and Development, New London, CT 06320, USA
(3) USDA/ARS Children’s Nutrition Research Center, Departments of Pediatrics and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
(4) Departments of Medicine and Molecular and Cellular Biology, Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
Received: 2 January 2006 Accepted: 4 January 2006 Published online: 16 March 2006

Summary 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.
Keywords breast cancer - growth hormone - IGF-I - mammary gland - pegvisomant