Comparative Endocrinology Research Group

Comparative endocrinology allows researchers to find novel roles for known hormones or even discover new hormones. Simpler ancestral animals may have a single hormone that has only one function or task and, as animals have evolved, they now may have several hormones that do that one function. This multiplication of hormones ensures survival of that species.

Our research group is interested in the evolution of calcium regulating hormones and the roles in normal and tumour growth. The hormone that interests us the most is parathyroid hormone-related protein (PTHrP) which we have demonstrated in a range of fish and sharks. PTHrP has been shown to be important in a number of cancers in humans and our group is looking at how the comparative approach can shed more light on PTHrP’s role in cancer, particularly breast and bone cancer.

The team

• Dr Janine Danks, Laboratory Chief
• Kristi Milley, PhD student
• Haley Gunn, PhD student
• Dr Roula Papadopoulos, Pathology consultant

Past laboratory members

• Alex Ibrahim - MSc student- 2007
• Yang Liu - Honours student-2008

Collaborators

• Dr Linda Abrahams, The University of Melbourne, Veterinary Science, Werribee
• Prof Venkatesh Byrappa, Institute of Molecular and Cell Biology, Singapore
• Dr Rachel Davey, The University of Melbourne, Department of Medicine, Austin Health, Heidelberg
• Prof Eleanor Mackie, The University of Melbourne, Veterinary Science, Parkville
• Prof T.J Martin, St Vincent’s Institute of Medical Research, Fitzroy
• Prof Tom Rosol, University of Ohio, Veterinary Biosciences, Columbus, Ohio, USA
• Prof Jane Visvader, Walter and Eliza Hall Institute, Parkville
• Dr Carl Walkley, St Vincent’s Institute of Medical Research, Fitzroy
• Dr Tony Mustaers, St Vincent’s Institute of Medical Research, Fitzroy
• Prof Jeff Zajac, The University of Melbourne, Department of Medicine, Austin Health, Heidelberg

Current funding

Project Grant APP ID 620203, “Effects of Ephrin/Eph and PTHrP signalling on osteosarcoma” Prof. T.J. Martin (CIA), Dr C Walkley (CIB), Dr. J.A. Danks (CIC) ($623,500) 1/1/2010-31/12/2012

Research projects

1. Canine mammary tumours as a model for human breast cancer.

PTHrP has been localized in 60% of primary breast tumours (Southby et al, Cancer Res. 50:7710, 1990) and in 11/13 bony metastases (Powell et al, Cancer Res. 51:3059, 1990). In clinical studies it has been shown that the presence of PTHrP in primary tumours gives a better patient prognosis and a lower rate of metastasis to any site (Henderson et al, Cancer Res. 66:2250, 2006).

Better diagnostic and treatment tools have resulted in limited pathological material available for research and this has resulted in the search for new breast cancer models. Some groups have used transgenic animal models and others have suggested natural models, including canine mammary tumours (Rivera et al, Cancer Res. 69:8770, 2009). Dogs are considered a model of natural occurring breast cancer and they live in the same environment as humans.

In this study we are collecting canine mammary tumours (CMT) have been collected from four specialist veterinary pathology companies and over 100 veterinary surgeons in Victoria and Southern NSW. The large amount of canine mammary tissue is collected as part of normal treatment and this is allowing a direct comparison of full tumour histopathological samples with tissue arrays (TMA). These tumours were classifed pathologically using molecular subtyping,that has been suggested to better reflect patient prognosis (Perou et al, Nature 406:747, 2000) than the current typing by estrogen/progesterone receptor status. Sixty benign and twenty malignant CMTs had both PTHrP and parathyroid hormone receptor 1 (PTH1R) immunohistochemistry (IHC) carried out in both full tumour sections and TMAs. Polyclonal antisera to human PTHrP (1-14) and monoclonal antiserum to PTH1R have been used and there presence in the CMTs indicated that there was a relationship between the presence of PTHrP and the molecular subtypes. This could provide an explanation for the presence of PTHrP in the primary tumours and the association with a better patient prognosis.

2. The evolution of the vertebrate skeleton from cartilage to bone.

A bony skeleton has been considered a feature of highly evolved vertebrates including the most successful group, mammals. However, many vertebrates, including the jawless fish, sharks and rays have a predominantly cartilaginous skeleton.

The dogma is that the development of bone was crucial for the movement of vertebrates onto land. Bone not only provided a physical support but also a readily-accessible reservoir of calcium. Animals living in either a marine or freshwater environment have a constant supply of calcium and other ions. Land-dwelling vertebrates only have episodic access to calcium via their food intake and as calcium is required constantly terrestrial vertebrates have an absolute requirement for readily available calcium. Circulating calcium levels in every vertebrate are maintained at 2.1-2.8 mmol/l ((Dacke, 1979)) and are very tightly regulated. This regulation is one of the features that divide invertebrates from vertebrates. We have shown that the parathyroid hormone gene family, PTHrP and parathyroid hormone (PTH), are present in fish and sharks. The shark we have studied most recently is the elephant shark, Callorinchus milii. This species is found off the Victorian coast and recently its own genome has been sequenced (ESHark website). We are now looking at other genes in the pathways known to be important in bone formation, including the Wnt pathway.

3. Canine osteosarcoma: Is histological subtype is linked to patient outcome?

Osteosarcoma (OS) is the most common primary bone tumour, occurring predominantly in adolescents. OS has a rare presentation in humans accounting for only 2.4% of all childhood tumours. OS is naturally occurring in dogs, although it is 20 times more prevalent in dogs than humans. We will use canine OS as a model for the human disease. In this project we are currently vaildating the canine model using immunohistochemistry and whole genome screening. Next, the canine OS model will be used to investigate the controversial topic of the prognostic value of the histological classification of OS. Currently it is not known if the seven different histological subtypes have differing prognostic outcomes and so we hope to determine the patient outcome for each of the subtypes. This would allow the development of new targeted therapy based on histological subtype in the future, improving patient outcome.

Selected publications

• Henderson, M.A, Danks, J.A., Moseley, J.M., Slavin, J.L., Harris, T.L., McKinlay, M.R., Grill, V., Hopper, J.L. and Martin, T.J. Parathyroid hormone-related protein production by breast cancers associated with improved survival and reduction in bone metastases. J. Natl. Cancer Inst., 93:234-237, 2001. (IF: 13.844, cited 37)
• Trivett, M.K., Walker, T.I., Macmillan, D.L., Clement, J.G., Martin T.J. and Danks, J.A. Parathyroid hormone-related protein (PTHrP) production sites in elasmobranchs. J.Anat, 201:41-52, 2002. (IF: 2.072, cited 4)
• Danks, J.A., Ho, P.M.W., Notini, A.J., Katsis, F., Hoffmann, P., Kemp, B.E., Martin T.J. and Zajac, J.D. Identification of a parathyroid hormone in the fish, Fugu rubripes. J. Bone Miner. Res., 18:1326-1331, 2003. (IF: 6.043, cited 25)
• Hogan B.M., Danks, J.A., Layton, J.E., Hall, N.E., Heath J.K. and Lieschke, G.J. Duplicate zebrafish pth genes are expressed in the lateral line and central nervous system during embryogenesis. Endocrinology, 146:547-551, 2005. (IF: 5.063, cited 10) This paper was featured in the News and Views section of the journal.
• Trivett M.K., Potter I.C., Power G., Zhou H., Macmillan D.L., Martin T.J. and Danks J.A. Parathyroid hormone related protein (PTHrP) production in the lamprey Geotria australis: developmental and evolutionary perspectives. Development, Genes and Evolution 215: 553-563, 2005. (IF:2.266, cited 2)
• Martin T.J.,Danks J.A. and Henderson M.J. Parathyroid hormone-related protein and bone metastases. In “Textbook on Bone Metastases” eds. Jasmin C., Capanna R., Coleman R.E., Coia L.R, Salliant G., John Wiley and Sons Chichester UK, pp 27-41, 2005.
• Henderson, M.A, Danks, J.A., Slavin, J.L., Byrnes, G.B., Choong, P.F.M., Spillane, J.B., Hopper, J.L. and Martin, T.J. Parathyroid hormone-related protein localization in breast cancers predict improved prognosis: verification from a long-term prospective study. Cancer Research 66:2250-2256, 2006. (IF: 8.649, cited 21)
• McManus, J.F., Doust, E.A., Davey R.A., MacLean,H.E., Ma C., Sims, N.A., Bouxsein, M.L., Glatt, V., Zajac, J.D. and Danks, J.A. Intermittent Fugu parathyroid hormone 1 (1-34) is an anabolic bone agent in young male rats and osteopenic ovariectomized rats. Bone.42:1164-1174, 2008. (IF: 3.829, cited 1)
• Danks, J.A and Zajac, J.D. The parathyroid gland: from fish to man. Current Opinion in Nephrology and Hypertension 17:353-357, 2008 (IF: 4.137)
• Inoue, J.G., Miya, M., Lam, K., Tay, B-H., Danks, J.A., Bell, J., Walker, T.I., Venkatesh, B. (2010)Evolutionary origin and phylogeny of the modern holocephalans (Chondrichthyes: Chimaeriformes): A mitogenomic perspective. Molecular Biology and Evolution, 27:2576-2586, 2010 (IF: 9.782)
• Liu, Y., Ibrahim, A.S., Tay, B-H., Richardson, S.J., Walker, T.I., Bell, J., Brenner, S., Venkatesh, B. and Danks, J.A. Parathyroid gene family presence in a cartilaginous fish, the elephant shark (Callorhinchus milli) J. Bone Miner. Res., 25:2337-2347 (IF: 6.043)
• Danks, J.A., D’Souza, D.G., Gunn, H.J., Milley, K. M., Richardson, S.J. Evolution of the parathyroid hormone gene family and skeletal formation pathways. Gen. Comp. Endocrinol. 170:79-91, 2011 (IF: 1.736) (invited review for 50^th Anniversary edition of the journal)
• Danks, J.A. and Richardson S.J. Endocrinology and evolution: Lessons from comparative endocrinology. In “Oxford Textbook of Endocrinology”, ed Wass J.H., Oxford University Press, Oxford. 2^nd edn, 2011

Why not join us?

All enquiries about joining the group as Honours and Postgraduate students or as Post-doctoral Fellows should be directed to Janine.danks@rmit.edu.au