Higher Degree by Research Candidate
Adelaide Medical School
Faculty of Health and Medical Sciences
My research concerns the earliest events in mammary carcinogenesis, with a focus on the interactions of the immune system with mammary epithelium. Macrophages in the mammary gland can detect and destroy cancers or promote their establishment and growth. Efferocytosis of dying ductal epithelium by macrophages produces a tolerogenic microenvironment conducive to cancer growth. Inhibition of this process has the potential to modify macrophage response leading to destruction of nascent cancers.
Originally from California, I moved to Adelaide in 1989 and have worked in a number of different research institutions. The loss of my wife to breast cancer prompted me to commence PhD study in the hopes of finding a way to prevent this disease.
While breast cancer is the most commonly diagnosed cancer in women, it represents an even more serious disease in premenopausal women. Women under 40 are more likely to be diagnosed with triple negative cancer, a sub-type for which there are no targetted therapies available and are therefore treated with chemotherapy alone. As a result, young women face a poorer prognosis than women developing breast cancer later in life.
An important element in the development breast cancer is menstrual cycling. Women having children, having children at a young age, having more than one child and breastfeeding their babies are all factors that reduce the risk of developing breast cancer. And this is because all of these events stop the menstrual cycle. During the cycle, the ductal epithelial tissue in the breast proliferates and form structures called alveoli in preparation for a pregnancy. If no pregnancy eventuates, the alveolar structure become apoptotic and regress. Macrophages remove the dying alveoli and, in so doing, generate and anti-inflammatory microenvironment in the breast, which is similar to a wound-repair state. This involves tissue remodeling and angiogenesis, but also the suppression of pro-inflammatory immune surveillance that detects and destroys early neoplastic events. More menstrual cycles mean more proliferation and more opportunity for the accumulation of cell division-related mutations, which is exacerbated by the anti-inflammatory environment that allows cancers to take hold.
A key component in the removal of dying epithelium in the breast is the complement component C1q. C1q recognises phosphatidylserine and calreticulin on the surface of apoptotic cells and bridges them to macrophages via CD91 and CD93. In mouse models, the lack of C1q leads to a build-up of apoptotic cells in the mammary gland and a seven-fold decrease in the incidence of carcinogen-induced mammary tumours. This implies the lack of C1q allows normal immune surveillance during mammary gland regression and a decrease in mammary tumour development. It also presents an opportunity to develop a therapeutic intervention able to inhibit breast cancer formation. I am working to develop a monoclonal antibody for use as a breast cancer preventative agent as well as a possible treatment for triple negative disease in premenopausal young women. This antibody is currently in development and I have great hopes for its efficacy and translation to the clinic.
Year Citation 2012 Hardingham., Wrin, J., Shivasami, A., Tebbutt, N., & Price, T. (2012). BRAF V600E Mutation Detection Using High Resolution Probe Melting Analysis. In P. Hernandez-Rodriguez, & A. Gomez (Eds.), Polymerase Chain Reaction (pp. 143-156). Online: InTech.
Year Citation 2015 Tomita, Y., Dorward, H., Wrin, J., Vary, R., De Ieso, M., Yool, A., . . . Hardingham, J. (2015). The effect of aquaporin-5 knockdown on HT29 colon cancer cell proliferation and migration. In ANNALS OF ONCOLOGY Vol. 26 (pp. 4). Singapore, SINGAPORE: OXFORD UNIV PRESS. 2014 Price, T. J., Bruhn, M., Lee, C., Hardingham, J., Townsend, A. R., Mann, K., . . . Tebbutt, N. C. (2014). Correlation of PI3KCAand extended RAS gene mutation status with outcomes from the phase III AGITG MAX involving capecitabine (C) alone or in combination with bevacizumab (B) with or without mitomycin C (M) in advanced colorectal cancer (CRC).. In JOURNAL OF CLINICAL ONCOLOGY Vol. 32 (pp. 1 page). Chicago, IL: AMER SOC CLINICAL ONCOLOGY.
2012 Price, T., Hardingham, J., Lee, C., Townsend, A., Wrin, J., Wilson, K., . . . Tebbutt, N. (2012). PTEN AND ADVANCED COLORECTAL CANCER (CRC): ANALYSIS FROM THE PHASE III AGITG MAX TRIAL OF CAPECITABINE ALONE OR IN COMBINATION WITH BEVACIZUMAB +/- MITOMYCIN C. In ANNALS OF ONCOLOGY Vol. 23 (pp. 182). Vienna, AUSTRIA: OXFORD UNIV PRESS. 2010 Price, T., Hardingham, J., Lee, C., Weickhardt, A., Townsend, A., Wrin, J., . . . Tebbutt, N. (2010). IMPACT OF KRAS AND BRAF GENE MUTATION STATUS ON OUTCOMES FROM THE PHASE III AGITG MAX TRIAL OF CAPECITABINE (C) ALONE OR IN COMBINATION WITH BEVACIZUMAB (B) +/- MITOMYCIN C (M) IN ADVANCED COLORECTAL CANCER (CRC). In ANNALS OF ONCOLOGY Vol. 21 (pp. 198). Milan, ITALY: OXFORD UNIV PRESS.
Year Citation 2014 Price, T. J., Townsend, A. R., Bruhn, M., Lee, C., Wrin, J., Shivasami, A., . . . Hardingham, J. (2014). Assessment of IL-6, IL-8, bFGF, PDGF-BB, and VEGF-A as prognostic and predictive biomarkers for anti-VEGF in metastatic colorectal cancer (mCRC).. Poster session presented at the meeting of JOURNAL OF CLINICAL ONCOLOGY. San Francisco, CA: AMER SOC CLINICAL ONCOLOGY.
2013 Price, T., Hocking, C., Broadbridge, V., Wrin, J., Townsend, A., Tebbutt, N., . . . Hardingham, J. (2013). Can we accurately report PTEN status in advanced colorectal cancer?. Poster session presented at the meeting of European Cancer Congress 2013 Abstract Book, as published in European Journal of Cancer. Amsterdam, Netherlands: Elsevier.
2012 Price, T. J., Hardingham, J., Lee, C., Wrin, J., Townsend, A. R., Wilson, K., . . . Tebbutt, N. C. (2012). Analysis of PTEN in patients with advanced colorectal cancer (CRC) receiving capecitabine alone or in combination with bevacizumab with or without mitomycin C in the phase III AGITG MAX trial. Poster session presented at the meeting of JOURNAL OF CLINICAL ONCOLOGY. Chicago, IL: AMER SOC CLINICAL ONCOLOGY.
- Title: Breaking immune tolerance in triple negative breast cancer
- Funding scheme: ORG106963: THRF - Project Grant
- Description: Failure of the body’s immune system to attack a threat such as a mutated cell is known as immune tolerance, and is one of the key hurdles to overcome in both treating breast cancer and preventing its recurrence. Our laboratory has identified a new biological pathway active in breast cancer involving a protein called C1q, which can be targeted to break this tolerance. The aim of this project is to capitalize on this discovery to develop a new approach to breaking tolerance in triple negative cancer, a very aggressive subtype of breast cancer which is notoriously difficult to treat. In this project, we will study the biological interactions between immune system cells and cancer cells that cause tolerance to breast cancer. We will investigate how C1q acts to guide the immune system towards tolerance of cancer cells. We will also develop an anti-C1q antibody that inhibits C1q action that could be used in the future to treat patients with triple negative breast cancer.
- Funder name: The Hospital Research Foundation
- Funder reference: N/A
- Investigators: Ingman W; Evdokiou A; Wrin J
Reporting dates: 01 Jul 2017 to 30 Jun 2018
Date Role Committee Institution Country 2016 - 2019 Member ASI Day of Immunology Organising Committee University of Adelaide Australia 2016 - 2019 Member ASI Adelaide Immunology Retreat Organising Committee University of Adelaide Australia
Date Title Engagement Type Institution Country 2018 - 2018 ASI Day of Immunology Public Community Engagement University of Adelaide Australia 2017 - 2018 Mothers Day Classic Public Community Engagement University of Adelaide — 2017 - 2107 Mother's Day Classic Launch Public Community Engagement University of Adelaide Australia
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