Joseph Wrin

Mr Joseph Wrin

Higher Degree by Research Candidate

PhD 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.

  • 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

  • Position: PhD Candidate
  • Phone: 83134011
  • Email:
  • Campus: North Terrace
  • Building: TQEH - Basil Hetzel Institute, floor 1
  • Org Unit: Surgical Specialities

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