Training and Other Affiliations
General Research Description
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.
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
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
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.
have implications not only for carcinogenic processes leading to breast
cancer, but also for development of prostatic cancer, which shares many
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.
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,
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,
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.
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,
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,
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,
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.