Breast cancer is a multi-hormonal disease in which steroidal and polypeptide hormones are critical factors in tumorigenesis and/or neoplastic growth. Effects of hormones are mediated via receptors, cellular proteins displaying high affinity and specificity for their hormonal ligand. While the simpler concepts of single hormone responses remain valid, a more complex picture is emerging, with interrelations amongst hormones and recently, several growth factors acting via autocrine/paracrine mechanisms, all contributing to neoplastic growth. By utilizing two different well-characterized rodent mammary tumors, and study of these both in vivo and in vitro, we demonstrated that insulin is an important hormonal factors, which can have direct and/or facilitative roles, the latter role manifesting itself by interrelationships with estradiol and progesterone via insulin receptor modulation. This emerging hypothesis now requires better definition of discrete sites of hormonal action as regulatory agents at the receptor level and extension of the effects of these hormones to selected growth factors, having in common with insulin receptors a capability to phosphorylate tyrosines. We therefore propose to utilize these systems by selected experiments in vivo and in vitro to 1) ascertain alterations in insulin receptor tyrosine kinase activity by study of various hormonal perturbations that alter tumor growth in vivo and in vitro to provide new insight at this important regulatable site of hormone action and its relationship to tumor growth; 2) characterize and then determine whether EGF receptors are regulated by insulin and female sex steroids and whether such perturbations relate to tumor growth; 3) determine whether receptors for IGF-1, an insulin-like growth factor whose receptors are distinct and display tyrosine kinase activity, are present and functional in these mammary tumors, and are regulated by the same hormonal perturbations known to affect insulin receptors; and 4) to investigate the actions of insulin on phosphatidylinositol metabolism by study of the various components of the PI cycle, thereby providing data that would suggest a role for this cycle as a mediator of insulin action on tumor growth. By use of hormone-dependent and responsive models, elucidation of such hormonal interactions should provide new insight of regulatory events that affect mammary cancer growth.
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