This proposal describes a 5 year training program for the development of an academic career in biomedical sciences. This program will enhance critical skills for utilizing in vivo models as a tool for understanding complex human pathology. Dr. Linda Schuler, a recognized leader in the field of prolactin signaling, will mentor the principal investigator's scientific development. An advisory committee of highly- regarded scientists will provide guidance for this project as well as career advice. An estimate of 211,000 women in the United States will be diagnosed with invasive breast cancer this year. Although the focus for developing treatments has targeted hormonal signaling pathways, a critical gap exists in the knowledge of signaling cross talk among key factors that cooperate for dysregulated growth in this disease. Prolactin's (PRL) central role in mammary development, lactation, and involution has fueled interest in its signaling in breast cancer. The Schuler lab has generated transgenic mice that overexpress PRL under control of a mammary selective, non-hormonally responsive promoter, NRL. These mice develop mammary adenocarcinomas that are estrogen receptor alpha positive and negative, similar to human disease. Given the importance of estrogen and its receptor in the pathogenesis as well as treatment of this disease, this model is an excellent tool to study interactions between PRL and estrogen in disease development and progression., Another well-characterized mammary oncogene, transforming growth factor alpha (TGFa) has been correlated with estrogen receptor alpha negative breast tumors in humans and synergizes with PRL to induce mammary tumors in our transgenic model system. Using this model, we will investigate the hypothesis that circulating estrogen enhances the cooperative interaction of local mammary prolactin and TGFa to promote tumor development and progression.
The specific aims i nclude: 1) Examining the effect of post-pubertal ovarian estrogen on mammary lesion development, 2) Investigating the influence of estrogen on tumor progression once a lesion has developed, and 3) Identification of pathways of cooperative crosstalk among PRL, TGFa, and estrogen that may enhance carcinogenesis in vitro and in vivo. Together these studies will illuminate the cooperative roles of PRL, TGFa, and estrogen in the progression of breast cancer and could lead to useful diagnostic strategies and improved theraputic targets.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
7K01RR021858-03
Application #
7362396
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Moro, Manuel H
Project Start
2008-04-01
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
3
Fiscal Year
2008
Total Cost
$118,335
Indirect Cost
Name
Tufts University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Arendt, Lisa M; St Laurent, Jessica; Wronski, Ania et al. (2014) Human breast progenitor cell numbers are regulated by WNT and TBX3. PLoS One 9:e111442
Arendt, Lisa M; Keller, Patricia J; Skibinski, Adam et al. (2014) Anatomical localization of progenitor cells in human breast tissue reveals enrichment of uncommitted cells within immature lobules. Breast Cancer Res 16:453
McCready, Jessica; Arendt, Lisa M; Glover, Eugene et al. (2014) Pregnancy-associated breast cancers are driven by differences in adipose stromal cells present during lactation. Breast Cancer Res 16:R2
Arendt, Lisa M; McCready, Jessica; Keller, Patricia J et al. (2013) Obesity promotes breast cancer by CCL2-mediated macrophage recruitment and angiogenesis. Cancer Res 73:6080-93
Iyer, Vandana; Klebba, Ina; McCready, Jessica et al. (2012) Estrogen promotes ER-negative tumor growth and angiogenesis through mobilization of bone marrow-derived monocytes. Cancer Res 72:2705-13
Asher, Jennifer M; O'Leary, Kathleen A; Rugowski, Debra E et al. (2012) Prolactin promotes mammary pathogenesis independently from cyclin D1. Am J Pathol 181:294-302
Arendt, Lisa M; Rugowski, Debra E; Grafwallner-Huseth, Tara A et al. (2011) Prolactin-induced mouse mammary carcinomas model estrogen resistant luminal breast cancer. Breast Cancer Res 13:R11
Keller, Patrica J; Lin, Amy F; Arendt, Lisa M et al. (2010) Mapping the cellular and molecular heterogeneity of normal and malignant breast tissues and cultured cell lines. Breast Cancer Res 12:R87
Arendt, Lisa M; Rudnick, Jenny A; Keller, Patricia J et al. (2010) Stroma in breast development and disease. Semin Cell Dev Biol 21:11-8
McCready, Jessica; Arendt, Lisa M; Rudnick, Jenny A et al. (2010) The contribution of dynamic stromal remodeling during mammary development to breast carcinogenesis. Breast Cancer Res 12:205

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