Dr. Christine Pratt

NF-κB has critical roles in normal organogenesis, the immune system, and cancer. Research in Dr. Pratt’s lab over the past several years has focused on the role that NF-κB plays in normal mammary gland development and in breast cancer. To study this, she utilizes both mouse models and mammary epithelial and tumor cell lines to dissect relevant signaling pathways. Breast cancer models include oncogenic transgenes (SV40Tg and erbB2) and carcinogen induction (dimethyl-benzanthracene). The effect of concomitant deletion/mutation of factors that impinge on the NF-κB pathway - including upstream kinases, inhibitory proteins, and apoptotic regulatory factors, as well as NF-κB transgenic reporter mice - has facilitated the interrogation of the role of NF-κB in the development of breast cancers. Dr. Pratt also collaborates with pathologists to evaluate NF-κB pathway proteins as prognostic markers in pre-cancerous breast lesions in patients. Another interest includes novel small molecules that differentially interact with the estrogen receptors α and β and their potential for therapeutic applications.

Analysis of the mouse mammary gland as a whole mount in virgin mice and as a function of the number of days of gestation.

Mouse mammary gland whole mount analysis in virgin mice and days of pregnancy.

NF-κB protein family: immunohistochemistry of breast hyperplasia in a patient — NF-κB protein family: immunohistochemistry of patient breast hyperplasia

Dr. Pratt currently coordinates and teaches the majority of the only comprehensive pharmacology course at the University to third and fourth-year students from the Faculty of Science. She continues her longstanding teaching of the non-steroidal anti-inflammatory drugs to medical students. Dr. Pratt also developed the graduate course, “The Biology of Cancer” which she coordinates and teaches as well as “Signaling in Cancer Cells” and the graduate course, “Advanced Topics in Cancer”.

Dr. Pratt’s early finding that estrogen regulates the anti-apoptotic protein Bcl-2 was instrumental in understanding the mechanism of endocrine-targeted therapies in hormone-responsive breast cancers. This paper has been cited more than 400 times and has also spurred studies in other areas, including neurobiology, where the role of estrogen in neuronal protection has now been widely investigated.

Fluorescence-activated cell sorting of mouse mammary stem and progenitor cells

Most recently Dr. Pratt’s lab has discovered that the etiology of BRCA1 associated breast cancers derives from the propensity of BRCA1-deficient luminal progenitor cells to accumulate replication-associated DNA damage as a result of progesterone-induced proliferative signaling. The resulting induction of the DNA damage response activates NF-κB, which drives cells to continued proliferation independent of progesterone. This results in the accumulation of genetically unstable luminal progenitor cells. Patients with BRCA1 mutation typically develop hormone receptor negative breast cancers. Thus, for the first time, Dr. Pratt’s work explains the clinical phenomenon of reduced BRCA1 breast cancer risk after removal of the ovaries. From the chemoprevention perspective, her lab has also found that classes of NF-κB inhibitors can block this proliferation, both in vitro and in vivo, which may offer new hope for prevention to patient carriers of this mutation. Dr. Pratt is currently applying this general mechanism to other familial breast cancer genes, most of which encode proteins involved in DNA repair.

Series of events leading to breast cancer in BRCA1 mutation carriers

Dr. Pratt’s work has been supported by the Canadian Institutes for Health Research, Canadian Cancer Society Research Institute, The Cancer Research Society, the Canadian Breast Cancer Foundation and the Cancer Research Society Inc. Her lab currently has grant support from the Canadian Cancer Society Research Institute.

David Carr, Rosanna Lau, Alexandra D Hnatykiw, Gwendoline CD Ward, Manijeh Daneshmand, Miguel A Cabrita, MA Christine Pratt. cIAP2 Is an Independent Signaling and Survival Factor during Mammary Lactational Involution and Tumorigenesis. J Mammary Gland Biol Neoplasia. 2018 Sep;23(3):109-123. doi: 10.1007/s10911-018-9398-y. PMID: 29876871
Andrea Sau, Miguel A Cabrita, MA Christine Pratt. NF-κB at the Crossroads of Normal Mammary Gland Biology and the Pathogenesis and Prevention of BRCA1-Mutated Breast Cancer. Cancer Prev Res (Phila). 2018 Feb;11(2):69-80. doi: 10.1158/1940-6207.CAPR-17-0225. Review. PMID: 29101208
Andrea Sau, Rosanna Lau, Miguel A Cabrita, Emma Nolan, Peter A Crooks, Jane E Visvader, MA Christine Pratt MA. Persistent Activation of NF-κB in BRCA1-Deficient Mammary Progenitors Drives Aberrant Proliferation and Accumulation of DNA Damage. Cell Stem Cell. 2016 Jul 7;19(1):52-65. doi: 10.1016/j.stem.2016.05.003 PMID: 27292187
Samantha C Ruddy, Rosanna Lau, Miguel A Cabrita, Chelsea McGregor, Bruce C McKay, Leigh C Murphy, James S Wright, Tony Durst, MA Christine Pratt. Preferential estrogen receptor β ligands reduce Bcl-2 expression in hormone-resistant breast cancer cells to increase autophagy. Molecular Cancer Therapeutics. 2014 Jul;13(7):1882-93. doi: 10.1158/1535-7163. PMID: 24785256
Chelsea McGregor, Andrea Sau A, Samantha C Ruddy, D Leung, Murray Webb, Tony Durst T, James S Wright, Diane Lagace, MA Christine Pratt. Novel ligands balance estrogen receptor β and α agonism for safe and effective suppression of the vasomotor response in the ovariectomized female rat model of menopause. Endocrinology. 2014 Jul;155(7):2480-91. doi: 10.1210/en.2013-1976. PMID: 24823389
MA Christine Pratt*, Emma Tibbo, Susan J Robertson, Diedre Jansson, K Hurst, Carole Perez-Iratxeta, Rosanna Lau R, Min Ying Niu. The canonical NF-kappaB pathway is required for formation of luminal mammary neoplasias and is activated in the mammary progenitor population. Oncogene. 2009 Jul 30;28(30):2710-22. doi: 10.1038/onc.2009.131. PMID: 19483731 * senior author

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