Too, Catherine K. L. - Dalhousie University - Department of Biochemistry & Molecular Biology

研究领域

Novel prolactin-regulated genes in breast and prostate cancers We are interested in prolactin (PRL) receptor (PRLR) action in PRL-responsive tumours such as breast and prostate cancers. Our long-term goal is to elucidate the signal-transduction pathways of the PRLR and identify crosstalk between the PRLR and other signaling pathways. PRL, secreted by the anterior pituitary gland, acts as a classical endocrine hormone to regulate many physiological processes, e.g., osmoregulation, growth/development, reproduction, and immunoregulation. PRL, secreted by extra-pituitary tissues (e.g., normal and malignant mammary, prostate, and lymphoid tissues), can act as an autocrine/paracrine growth factor to stimulate cell growth. These actions of PRL are mediated by the PRLR which is found in most tissues in our body, including malignant breast and prostate tumours. Our studies are focused on identifying and characterizing novel PRL-regulated genes and their role(s) in PRLR signal transduction, cell proliferation, and cell death. We have research collaborations with clinicians working on breast and prostate cancers in the Depts of Pathology and Urology, Dalhousie University. Androgen and prolactin receptor interaction in breast and prostate cancers We are also studying the action of androgens, the androgen receptor (AR), and AR interaction with the PRLR in breast and prostate cancer cells which express PRLRs and ARs abundantly. Our recent studies show that the AR and PRLR work together to regulate specific genes that can promote survival of both cancer cell types. We have reported that combined inhibition of the AR and PRLR in prostate cancers is a more effective therapy to inhibit prostate cancer cell growth than inhibition of the AR alone. Our current studies focus on the identification of new androgen and PRL target genes that act together to promote tumour cell survival and disease progression.

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Thomas, L.N., Chedrawe, E.R., Barnes, P.J. and Too, C.K.L., (2017) Prolactin/androgen-inducible carboxypeptidase-D increases with nitrotyrosine and Ki67 for breast cancer progression in vivo, and upregulates progression markers VEGF-C and Runx2 in vitro. Breast Cancer Research and Treatment (in press): Too, C.K.L. and Abdelmagid, S.A. , (2016) L-Arginine uptake and its role in the survival of breast cancer cells. In: L-Arginine in Clinical Nutrition (Eds: VB Patel, VR Preedy and R Rajendram. Series Ed: A Bendich. Humana Press) Chap. 20:253-268 [Article] Jha, A., Yadav, Y., Naidu, A.B., Rao, V.K., Kumar, A., Parmar, V.S., MacDonald, W.J., Too, C.K.L., Balzarini, J., Barden, C.J. and Cameron, T.S., (2015) Design, synthesis and bioevaluation of novel 6-(4-hydroxypiperidino)naphthalen-2-ol-based potential Selective Estrogen Receptor Modulators for breast cancer. Eur. J. Med. Chem. 92:103-114 [PubMed] [Article] Thomas, L.N., Merrimen, J., Bell, D.G., Rendon, R. and Too, C.K.L., (2015) Prolactin- and testosterone-induced carboxypeptidase-D correlates with increased nitrotyrosines and Ki67 in prostate cancer. The Prostate 75:1726-1736 [PubMed] [Article] McDonald, W.J., Thomas, L.N., Koirala, S. and Too, C.K.L., (2014) Progestin-inducible EDD E3 ubiquitin ligase binds to α4 phosphoprotein to regulate ubiquitination and degradation of protein phosphatase PP2Ac. Mol. Cell. Endocrinol. (382):254-261. [PubMed] [Article] Thomas, L.N., Merrimen, J., Bell, D.G., Rendon, R., Goffin, V. and Too, C.K.L., (2014) Carboxypeptidase-D is elevated in prostate cancer and its anti-apoptotic activity is abolished by combined androgen and prolactin receptor targeting The Prostate 74:732-742. [PubMed] [Article] Koirala, S., Thomas, L.N. and Too, C.K.L., (2014) Prolactin/Stat5 and androgen R1881 co-activate carboxypeptidase-D gene in breast cancer cells. Mol. Endocrinology 28:331-343. [PubMed] [Article] Thomas, L.N., Morehouse, T.J. and Too, C.K.L., (2012) Testosterone and prolactin increase carboxypeptidase-D and nitric oxide levels to promote survival of prostate cancer cells. The Prostate 72:450-460. [PubMed] [Article] Abdelmagid, S.A., Rickard, J.A., McDonald, W.J., Thomas, L.N and Too, C.K.L., (2011) CAT-1-mediated arginine uptake and regulation of nitric oxide synthases for the survival of human breast cancer cell lines. J. Cell. Biochem. 112:1084-1092. [PubMed] [Article] Yadav Y., MacLean E., Bhattacharyya A., Parmar V.S., Balzarini J., Barden C., Too C.K.L. and Jha A., (2011) Design, synthesis and bioevaluation of novel candidate selective estrogen receptor modulators. Eur. J. Med. Chem. 46:3858-3866. [PubMed] McDonald, M.J., Sangster, S.M., Moffat, L.D., Henderson, M.J. and Too, C.K.L., (2010) Alpha4 phosphoprotein interacts with EDD E3 ubiquitin ligase and poly(A)-binding protein. J. Cell. Biochem. 110:1123-1129. [PubMed] [Article] Thomas, L.N., Douglas, R.C., Rittmaster, R.S. and Too, C.K.L., (2009) Overexpression of 5α-reductase Type 1 causes increased sensitivity to low concentrations of testosterone in LnGK9 prostate cancer cells. The Prostate 69:595-602. [PubMed] [Article] Thomas, L.N., Douglas, R.C., Lazier, C.B., Gupta, R., Norman, R.W., Murphy, P.R., Rittmaster, R.S. and Too, C.K.L. , (2008) Levels of 5α-reductase type 1 and type 2 are increased in malignant but not adjacent benign tissues from high grade as compared to low grade prostate cancer J. Urology 179:147-151. [PubMed] [Article] Thomas, L.N., Douglas, R.C., Lazier, C.B., Too, C.K.L., Rittmaster, R.S. and Tindall, D.J., (2008) Type 1 and Type 2 5&alpha-reductase expression in the development and progression of prostate cancer. European Urology 53:244-252 (Review) [PubMed] [Article] Abdelmagid, S. A. Too, C. K. L., (2008) Prolactin and Estrogen Upregulate Carboxypeptidase-D to Promote Nitric Oxide Production and Survival of MCF-7 Breast Cancer Cells. Endocrinology 149:4821-4828. [PubMed] [Article] Nien, W. L., Dauphinee, S. M., Moffat, L. D. and Too, C. K. L., (2007) Overexpression of mTOR alpha4 phosphoprotein activates PP2A and increases Stat1a binding to PIAS1 Mol. Cell. Endocrinol. 263:10-17. [PubMed] [Article] Bishop, J.D., Nien, W.L., Dauphinee, S.M. and Too, C.K.L., (2006) Prolactin activates mTOR through phosphatidylinositol 3-kinase and stimulates phosphorylation of p70S6K and 4E-BP1 in lymphoma cells. J. Endocrinology 190:307-312. [PubMed] [Article] Matte, G., Sangster, S.M., Acker, M., Hudgins, M. and Too, C.K.L., (2005) Characterization of 123I-iodo-alpha-methyltyrosine transport in rat lymphoma cells. Nuclear Medicine and Biology 32:67-73. [PubMed] [Article] Baguma-Nibasheka, M., Li, A.W., Osman, M.S., Geldenhuys, L., Casson, A.G., Too C.K.L. and Murphy, P.R. , (2005) Co-expression and regulation of the FGF-2 and FGF antisense genes in leukemic cells. Leukemia Res. 29:423-433. [PubMed] Dauphinee S.M., Ma M. and Too C.K.L. , (2005) Role of O-linked beta-N-acetylglucosamine modification in the subcellular distribution of alpha4 phosphoprotein and Sp1 in rat lymphoma cells. J. Cell. Biochem. 96:579-588. [PubMed] [Article] O'Malley, P.G.P., Sangster, S.M., Abdelmagid, S.A., Bearne, S.L. and Too, C.K.L.*, (2005) Characterizaion of a novel, cytokine-inducible carboxypeptidase-D isoform in hematopoietic tumor cells. Biochem J. 390:665-673. [PubMed] [Article] Vickaryous, N., Teh, E., Stewart, B., Dolphin, P.J., Too, C.K.L., and McLeod, R.S., (2003) Deletion of N-terminal amino acids from human lecithin:cholesterol acyltransferase differentially affects enzyme activity toward alpha- and beta-substrate lipoproteins. Biochim et Biophys Acta 1646:164-172. [PubMed] [Article] Boudreau, R.T.M., Sangster, S.M., Johnson, L.M., Dauphinee, S., Li, A.W. and Too, C.K.L., (2002) Implication of alpha4 phosphoprotein and rapamycin-sensitive mTOR pathway in prolactin receptor signalling. J. Endocrinology 173:493-506. [PubMed] [Article] Murphy, P.R., Limoges, M., Dodd, F., Boudreau, R.T.M., Too, C.K.L., (2001) FGF-2 stimulates endothelial nitric oxide synthase expression and inhibits apoptosis by a nitric oxide-dependent pathway in Nb2 lymphoma cells. Endocrinology 142:81-88. [PubMed] [Article] Too, C.K.L., Vickaryous, N., Boudreau, R.T.M. and Sangster, S.M., (2001) Identification and nuclear localization of a novel prolactin and cytokine-responsive carboxypeptidase D. Endocrinology 142:1357-1367. [PubMed] [Article]