|Divisova, Jana - BAYLOR COLLEGE MED|
|Kuiatse, Isere - PFIZER GLOBAL RES. & DEV.|
|Lazard, Zawaunyka - BAYLOR COLLEGE MED|
|Weiss, Heidi - BAYLOR COLLEGE MED|
|Vreeland, Franzanne - BAYLOR COLLEGE MED|
|Schiff, Rachel - BAYLOR COLLEGE MED|
|Osborne, C - BAYLOR COLLEGE MED|
|Lee, Adrian - BAYLOR COLLEGE MED|
Submitted to: Breast Cancer Research and Treatment
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: March 1, 2006
Publication Date: May 1, 2006
Citation: Divisova, J., Kuiatse, I., Lazard, Z., Weiss, H., Vreeland, F., Hadsell, D.L., Schiff, R., Osborne, C.K., Lee, A.V. 2006. The growth hormone receptor antagonist pegvisomant blocks both mammary gland development and MCF-7 breast cancer xenograft growth. Breast Cancer Research and Treatment. 98(3):315-327. Interpretive Summary: Development of the mammary gland is regulated by ovarian and pituitary hormones. Studies indicate that some of the effects of these hormones are mediated through secondary effects mediated by hormone-responsive growth factor molecules. Insulin-like growth factor I is a growth factor that is responsive to growth hormone and stimulates both normal mammary gland development and the growth of mammary tumors. This study demonstrates that a drug, pegvisomant, which inhibits the activity of growth hormone, causes a reduction of mammary gland development that is linked with decreased expression and secretion of insulin-like growth factor I. Along with this reduction, the activity of signaling proteins in the mammary gland that are known to mediate the actions of IGF-I are also reduced. This study suggests that inhibition of growth hormone action through specific drugs may be useful in treating some breast cancers.
Technical Abstract: 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((R)), 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 up to 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 may be useful for the prevention and/or treatment of estrogen receptor positive breast cancer.