Research in my laboratory is concerned with the growth factor activities of the hormone prolactin. These growth factor activities occur in many tissues including the pituitary, breast, endocrine pancreas, liver, prostate, and cells of the immune system. Although most prolactin is produced by the pituitary, some is produced in these other tissues where it may act as an autocrine or paracrine growth factor. In four of these tissues we have demonstrated antagonism between unmodified and phosphorylated prolactin in the regulation of growth, an antagonism which can be disturbed, leading to abnormal cell proliferation. In the case of the prostate, we have demonstrated that a molecular mimic of phosphorylated prolactin effectively inhibits metastases and growth of the primary tumor of late stage human prostate cancer cells in an animal model. Clinical trials will begin shortly. Other projects include effects of the molecular mimic on the development and progression of breast cancer and pituitary tumors. Thus we investigate the posttranslational modification of prolactin, the regulation of prolactin release, prolactin-receptor interactions, signal transduction and effects on gene transcription in each of these tissues. The laboratory uses a wide spectrum of techniques ranging from microscopy to molecular biology to whole animal physiology, each of which may be applied to answer a particular question.
Fetal development involves rapid cell proliferation, marked regional apoptosis and differentiation of developing tissues. For each tissue in the developing fetus, stem cells exist which usually can give rise to either stromal or parenchymal components. Even after fully functional differentiation has been achieved, however, many, if not all, tissues retain a population of stem cells. These stem cells may be called upon to replace damaged cells throughout life or they may function as a continual source of precursors for tissues that undergo cyclic growth and involution, such as the mammary gland . As a result of their less-differentiated nature and their capacity for self-renewal, stem cells are considered more likely to be transformed by carcinogen assault and therefore to give rise to tumors. The stem cells of all tissues are laid down during fetal development and are programmed by the maternal/fetal physiological milieu. Stressors to maternal physiology produce adaptive changes in the fetus, the consequences of which may include altered programming of stem cells. These changes in stem cell programming may, in turn, change susceptibility to growth promotion or apoptosis, leading to altered susceptibility to tumor formation.
In this study, we ask whether altered prolactin exposure during fetal life changes the level of expression of genes associated with cell proliferation or anti-apoptotic pathways in the adult mammary gland. Our hypothesis states that an alteration in fetal PRL exposure will affect susceptibility to breast cancer in adult offspring.
See publications on PubMed
Chen, T.J., C.Y.-B. Kuo, K.F. Tsai, J.-W. Liu, D.-Y. Chen and A.M. Walker. 1998. Development of recombinant human prolactin receptor antagonists by molecular mimicry of the phosphorylated hormone.
Endocrinology 139: 609-616.
Kuo, C.Y.-B., D. Coss and A.M. Walker. 1998. Prolactin receptor antagonists. Endocrine 9: 121-131.
Coss, D., C.B. Kuo, L. Yang, P. Ingleton, R. Luben and A.M. Walker. 1999. Dissociation of JAK 2 and STAT 5 activation after treatment of Nb2 cells with a molecular mimic of phosphorylated prolactin.
Endocrinology 140: 5087-5094.
Coss, D.J., L.L. Yang, C.B. Kuo, X.L. Xu, R.A. Luben, and A.M. Walker. 2000. Effects of prolactin on osteoblast alkaline phosphatase and bone formation in the developing rat. Am. J. Physiol. Endocrinol. Metab. 279, E1216-E1225.
Yang, L., C.B. Kuo, Y. Liu, D. Coss, X.L. Xu, C. Chen, M.L. Oster-Granite, and A.M. Walker. 2001. Administration of unmodified prolactin (U-PRL) and a molecular mimic of phosphorylated prolactin (PP-PRL) during rat pregnancy provides evidence that the U-PRL:PP-PRL ratio is crucial to the normal development of pup tissue. J. Endocrinol. 168: 227-238.
Bridges, R.S., B.A. Rigero, E.M. Byrnes, L. Yang, and A.M. Walker. 2001. Central infusions of the recombinant human prolactin receptor antagonist, S179D-PRL, delay the onset of maternal behavior in steroid-primed nulliparous female rats. Endocrinology 142: 730-739.
Warner, M.D., A. Walker, C. D'Souza, D. Lee, D. Nasseri, and C.A. Peabody. 2001. Prolactin bioassay in unmedicated schizophrenic patients. Psychiatry Res. 102: 249-254.
Lorenson, M.Y. and A.M. Walker. 2001. Structure-function relationships in prolactin. In Prolactin (Kluwer Academic Publishers, Massachusetts) N. D. Horseman editor, p. 181-283.