Adult female mammary development starts at puberty and is controlled by tightly regulated cross-talk between a group of
hormones and
growth factors. Although
estrogen is the initial driving force and is joined by luteal phase
progesterone, both of these
hormones require GH-induced
IGF-I in the mammary gland in order to act. The same group of
hormones, when experimentally perturbed, can lead to development of hyperplastic lesions and increase the chances, or be precursors, of mammary
carcinoma. For example, systemic administration of GH or
IGF-I causes mammary
hyperplasia, and overproduction of
IGF-I in transgenic animals can cause the development of usual or atypical
hyperplasias and sometimes
carcinoma. Although studies have clearly demonstrated the transforming potential of both GH and
IGF-I receptor in cell culture and in animals, debate remains as to whether their main role is actually instructive or permissive in progression to
cancer in vivo. Genetic imprinting has been shown to occur in precursor lesions as early as atypical
hyperplasia in women. Thus, the concept of progression from normal development to
cancer through precursor lesions sensitive to
hormones and
growth factors discussed above is gaining support in humans as well as in animal models. Indeed, elevation of
estrogen receptor, GH,
IGF-I, and
IGF-I receptor during progression suggests a role for these pathways in this process. New agents targeting the GH/
IGF-I axis may provide a novel means to block formation and progression of precursor lesions to overt
carcinoma. A novel
somatostatin analog has recently been shown to prevent mammary development in rats via targeted
IGF-I action inhibition at the mammary gland. Similarly,
pegvisomant, a GH antagonist, and other
IGF-I antagonists such as
IGF binding proteins 1 and 5 also block mammary gland development. It is, therefore, possible that inhibition of
IGF-I action, or perhaps GH, in the mammary gland may eventually play a role in
breast cancer chemoprevention by preventing actions of both
estrogen and
progesterone, especially in women at extremely high risk for developing
breast cancer such as BRCA gene 1 or 2 mutations.