Catherine K. L. Too

Education

• PhD, University of Hawaii

Academic Positions

• Department member 1994 - 2022
• Senior Scientist, Beatrice Hunter Cancer Research Institute
  

Research Topics

Polypeptide and Steroid Hormone Action: Tumour Growth/Apoptosis

Research

Novel prolactin-regulated genes in breast and prostate cancers

We study 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 PRLR and other signalling 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), acts as an autocrine/paracrine growth factor to stimulate cell growth. These actions of PRL are mediated by PRLR which is found in most tissues in our body, as well as in breast and prostate tumours. Our studies focus on identifying and characterizing novel PRL-regulated genes and their roles in PRLR signal transduction and tumour progression. We collaborate with clinicians working on breast and prostate cancers in the Departments of Pathology and Urology, Dalhousie University.

Androgen and prolactin receptor interactions in cancers

We study the action of androgens, the androgen receptor (AR), and AR-PRLR interaction in breast and prostate cancer cells which express both receptors abundantly. Our studies show that the AR and PRLR work together to regulate specific genes that promote survival of both cancer types. We have reported that combined inhibition of the AR and PRLR in prostate cancers is a more effective therapy than inhibition of the AR alone. Our current studies focus on new androgen and PRL target genes that act together to promote tumour cell survival, inhibit cell death, and disease progression.

Keywords:

prolactin, androgens, estrogen, signal transduction, breast and prostate cancers

Publications

1. Bharadwaj A, Dahn ML, Liu R-Z, Colp P, Thomas LN, Holloway R, Marignani PA, Too CKL, Barnes P, Godbout R, Marcato P and Waisman D. (2020). S100A10 has a critical regulatory function in mammary tumor growth and metastasis: Insights using MMTV-PyMT oncomice and clinical patient sample analysis. Cancers. 12: 3673; [Article]
2. MacDonald TM, Thomas LN, Gupta A, Barnes PJ and Too CKL (2020) Prolactin and androgen R1881 induce pro-survival carboxypeptidase-D and EDD E3 ligase in triple-negative and HER2+ breast cancer. Am J Cancer Res:10:1321-1343 [PubMed]
3. MacDonald, T.M., Thomas, L.N., Daze, E, Marignani, P., Barnes, P.J. and Too, C.K.L., (2019) Prolactin-inducible EDD E3 ubiquitin ligase promotes TORC1 signalling, anti-apoptotic protein expression, and drug resistance in breast cancer cells Am. J. Cancer Res. 9:1484-1503 [Article]
4. 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 164:27-40 [PubMed] [Article]
5. Arumuggam, N., Melong, N., Too, C.K.L., Berman, J.N. and Rupasinghe, H.P.V., (2017) Phloridzin docosahexaenoate, a novel flavonoid derivative, suppresses growth and induces apoptosis in T-cell acute lymphoblastic leukemia cells. Am. J. Cancer Res. 7:2452-2464 [Article]
6. 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]
7. 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]
8. 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]
9. 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]
10. 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]
11. 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]
12. 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]
13. 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]
14. 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]
15. 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]
16. 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]
17. 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]
18. 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]
19. 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]
20. 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]
21. 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]
22. 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]
23. 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]
24. 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]
25. 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]
26. 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]
27. 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]
28. 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]
29. 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]
30. Johnson, L.M. and Too, C.K.L., (2001) Prolactin, interleukin-2 and FGF-2 stimulate expression, nuclear distribution and DNA-binding of rat homolog of pombe Cdc5 in Nb2 T lymphoma cells. Mol. Cell. Endocrinol. 184:151-161. [PubMed] [Article]
31. Dodd, F., Limoges, M., Boudreau, R.T.M., Rowden, G., Murphy, P.R. and Too, C.K.L., (2000) L-arginine inhibits apoptosis via an NO-dependent mechanism in Nb2 lymphoma cells. J. Cell. Biochemistry 77:624-634. [PubMed] [Article]