Linda Schuler

Linda Schuler
General Research Description

Breast Cancer

The physiologic growth, differentiation and functional activity of the breast are orchestrated by a network of hormones, growth factors, and developmental regulators. Not surprisingly, many of these same factors have been found to play critically important roles in the development and progression of breast cancer. Understanding this interplay can lead to effective specific therapeutic approaches, minimizing side effects to patients, as well as potential preventative strategies.

Transcript profiling has enabled division of breast cancers into subtypes that may have different etiologies and may be susceptible to specifically targeted therapies. So-called “luminal” breast cancers [those that express estrogen receptor alpha (ERa+)] comprise about 75% of breast tumors. Although therapies directed at ERa are quite effective for this subtype, these regimens fail in about 25% of patients, who either are initially resistant or later develop resistance. Thus, understanding the pathogenesis and progression of luminal breast cancer would save the lives of many women.

Prolactin is a principle regulator of mammary epithelial proliferation and differentiation, consistent with a key role in breast cancer. Recent epidemiologic studies support its importance in “luminal” tumors. Elevated circulating prolactin is associated with a higher risk for development of this type of tumor, established tumors express higher levels of prolactin receptors than adjacent normal tissue, and evidence for prolactin activity is associated with disease progression and resistance to endocrine and conventional chemotherapies.

In order to understand the mechanisms whereby prolactin contributes to breast cancer, we have developed unique systems. Our transgenic mouse model, NRL-PRL, is one of the very few mouse models of clinical luminal breast cancer. This model enables us to examine the effects of prolactin on mammary stem and progenitor cells, as well as cancer stem cells. In conjunction with other transgenic and knockout models, we can examine crosstalk with identified oncogenic factors in the dynamic in vivo physiologic context. Our cell culture models facilitate molecular dissection of implicated signaling pathways, roles of cell context, including extracellular matrix, and mechanisms of interactions with other hormones and growth factors, including receptor trafficking.

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

Recent Publications

Sakamoto, K., A.A. Triplett, L.A. Schuler, K.-U. Wagner. Jak2 is required for the initiation but not maintenance of prolactin-induced mammary cancer, Oncogene 29:5359-5369, 2010.

Carver, K.C., T.M. Piazza and L.A. Schuler. Prolactin enhances IGF-IR phosphorylation by decreasing its association with the tyrosine phosphatase SHP-2 in MCF-7 breast cancer cells. J. Biol. Chem. 285:8003-8012, 2010.

Schuler, L.A. and A.P. Auger. Psychosocially influenced cancer: diverse early-life stress experiences and links to breast cancer. Cancer Prev Res 3:1365-1370, 2010.

Hasen, N.S., K.A. O’Leary, A.P. Auger and L.A. Schuler. Social isolation reduces mammary development, tumor incidence and expression of epigenetic regulators in wild type and p53-heterozygotic mice. Cancer Prev Res 3:620-629, 2010.

Arendt, L.M., L.C. Evans, D.E. Rugowski, M.J. Garcia-Barchino, H. Rui, and L.A. Schuler. Ovarian hormones are not required for PRL-induced mammary tumorigenesis, but estrogen enhances neoplastic processes, J. Endocrinol. 203: 99-110, 2009.

Piazza, T.M., J-C. Lu, K.C. Carver and L.A. Schuler. Src family kinases accelerate prolactin receptor internalization, modulating trafficking and signaling in breast cancer cells. Mol. Endocrinol. 23: 202-212, 2009.

Arendt, L.M., T.L. Grafwallner-Huseth, and L.A. Schuler. Prolactin and growth factor crosstalk reduces mammary estrogen responsiveness despite elevated ER expression. Am. J. Pathol. 174:1065-1074, 2009.

Regehr, K. J., M. Domenech, J.T. Koepsel, K. C. Carver, S. J. Ellison-Zelski, W. L. Murphy, L. A. Schuler, E. T. Alarid, and D. J. Beebe, Biological implications of polydimethylsiloxane-based microfluidic cell culture, Lab on a Chip 9:2132-2139, 2009.

Carver, K.C., L.M. Arendt and L.A. Schuler. Complex prolactin crosstalk in breast cancer: new therapeutic implications. Mol. Cell. Endocrinol. 307:1-7, 2009.

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

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.

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.

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 TGF transgenic mice progresses with progesterone receptor loss, Oncogene 26:5238-5246, 2007.

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.

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 signals to c-fos. Mol. Endocrinol. 19:1765-1778, 2005.

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