Linda Schuler
The Role of Prolactin in Mammary Cancer

Prolactin is an important regulator of mammary gland differentiation and growth. A role for this hormone in human breast cancer is supported by the observations of increased prolactin receptors in breast tumors compared to normal tissue, and the correlation of circulating prolactin with disease incidence. The diverse roles of this hormone in the normal gland suggest that its actions in breast cancer also are likely to be complex, involving multiple signaling pathways and dependency on hormone and growth factor context.

We have developed unique models to examine signaling pathways and cross talk in vitro and the net outcome of these processes in a physiologic context in vivo. We have demonstrated that prolactin is able to stimulate cell cycle progression by altering levels of cell cycle regulators in a manner that is distinct from other mammary mitogens, including estrogens and EGF. We have also shown that overexpression of prolactin within mammary epithelial cells in vivo in transgenic mice is sufficient to cause mammary tumors, and potentiates the actions of other mammary oncogenes. Current work employs a variety of technologies to identify the different signaling pathways that prolactin may use depending on the stage of neoplasia and cell context, and elucidate cellular mechanisms of interactions with other hormones and growth factors.

These studies have implications not only for carcinogenic processes leading to breast cancer, but also for development of hormone dependent prostatic cancer, which shares many underlying processes.

Publications:

Clevenger, C.V., P. Furth, S. Hankinson, and L.A. Schuler. The role of prolactin in mammary carcinoma. Endocrine Rev. 24:1-27, 2003.

Schroeder, M.D., T. Rose-Hellekant, E. Sandgren and L.A. Schuler. Dysregulation of STATs 1,3,and 5 and prolactin receptors by overexpression of mammary TGFα, Mol. Cell. Endocrinol. 175: 173-183, 2001.

Schroeder, M., J. Symowicz, and L.A. Schuler. Prolactin modulates cell cycle regulators in mammary epithelial tumor cells, Mol. Endocrinol. 16:45-57, 2002.

Brockman, J.L., M.D. Schroeder and L.A. Schuler. Prolactin stimulation of cyclin D1 transcription via the JAK-STAT pathway, Mol. Endocrinol. 16: 774-784, 2002.

Rose-Hellekant, T.A., L.M. Arendt, M.D. Schroeder, K. Gilchrist, E.P. Sandgren and L.A. Schuler. Prolactin induces ERα positive and ERα negative mammary cancer in transgenic mice, Oncogene 22:4664-4674, 2003.

Schroeder, M.D., J.L. Brockman, A.M. Walker, and L.A. Schuler. Inhibition of PRL induced proliferative signals in mammary tumor cells by a molecular mimic of phosphorylated PRL, S179D-PRL, Endocrinology 144:5300-5307, 2003. [Abstract]

Gutzman, J.H., K.K. Miller and L.A. Schuler. Endogenous hPRL and not exogenous hPRL induces ERα and PRLR expression and increases estrogen responsiveness in breast cancer cells, J. Steroid Biochem. Mol. Biol. 88:69-877, 2004. [Abstract]

Karp, C.M., H. Pan, M. Zhang, D.J. Buckley, L.A. Schuler, and A.R. Buckley. Identification of HRPAP20: a novel phosphoprotein that enhances growth and survival in hormone-responsive tumors, Cancer Res. 64:1016-1025, 2004. [Abstract]

Gutzman, J.H., D.E. Rugowski, M.D. Schroeder, J.J. Watters and L.A. Schuler. Multiple kinase cascades mediate prolactin signals to Activating Protein-1 in breast cancer cells, Mol. Endocrinol. 18: 3064-3075, 2004. [Abstract]

Gutzman, J.H., S.E. Nikolai, D.E. Rugowski, J.J. Watters and L.A. Schuler. Prolactin and estrogen enhance the activity of Activating Protein-1 in breast cancer cells: role of ERK1/2 mediated signals to c-fos, Mol. Endocrinol. 19:1765-1778, 2005. [Abstract]

Brockman, J.L. and L.A. Schuler. Prolactin signals via Stat5 and Oct-1 to the proximal Cyclin D1 promoter. Mol. Cell. Endocrinol. 239:45-53, 2005. [Abstract]

Arendt, L.M., T.A. Rose-Hellekant, E.P. Sandgren and L.A. Schuler. Prolactin potentiates TGFα induction of mammary neoplasia in transgenic mice. Am.J. Pathol. 168:1365-1374, 2006. [Abstract]

Rose-Hellekant, T.A., M.D. Schroeder, J.L. Brockman, O. Zhdankin, R. Bolstad, K.S. Chen, M.N. Gould, L.A. Schuler, E.P. Sandgren. Estrogen receptor positive mammary tumorigenesis in TGFα transgenic mice progresses with progesterone receptor loss, Oncogene 26:5238-5246, 2007. [Abstract]

Gutzman, J.H., D.E. Rugowski, S.E. Nikolai, L.A. Schuler. Stat5 activation inhibits prolactin-induced AP-1 activity: distinct prolactin initiated signals in tumorigenesis dependent on cell context, Oncogene 26:6341-6348, 2007.[Abstract]

Arendt, L.M. and L.A. Schuler. Prolactin drives ERα-dependent ductal expansion and synergizes with TGFα to induce mammary tumors in males. Am. J. Pathol., 172:194-202, 2008. [Abstract]

Carver, K.C. and L.A. Schuler. Prolactin does not require insulin-like growth factor (IGF) intermediates, but synergizes with IGF-I in human breast cancer cells. Mol. Cancer Res. 6:634-643, 2008. [Abstract]

Arendt, L.M. and L. A. Schuler. Transgenic models to study actions of prolactin in mammary neoplasia. J. Mammary Gland Biol. Neoplasia 13:29-40, 2008. [Abstract]

Arendt, L.M., T.L. Grafwallner-Huseth, and L.A. Schuler. Mammary prolactin and TGFα cooperatively enhance ERα expression while diminishing estrogen responsiveness in transgenic mice. Submitted.