NUTRITION DURING PREGNANCY, LACTATION, INFANCY, AND CHILDHOOD
Location: Children Nutrition Research Center (Houston, Tx)
Title: The growth hormone receptor antagonist pegvisomant blocks both mammary gland development and MCF-7 breast cancer xenograft growth.
| 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.
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.