Date of Award

2011

Document type

Thesis

Degree Name

MD (Medical Doctor)

First Supervisor

Dr Ann Hopkins

Funder/Sponsor

Breast Cancer Ireland, Beaumont Hospital Cancer Trust, Irish Government Programme for Research in Third Level Institutions.

Keywords

Breast Neoplasms, Immunoglobulins

Abstract

Breast cancer, a disease that arises from the epithelial cells within breast tissue, is a common illness that can affect all age groups. Each year it is diagnosed in an estimated 1 million women worldwide, and accounts for over 450,000 deaths. Despite advancements in breast cancer screening and treatment, breast cancer still remains one of the leading causes of female deaths worldwide. Breast cancer is a heterogeneous disease encompassing many subtypes, which differ both in terms of their molecular backgrounds and clinical prognosis. Cancer initiation and progression is a multistep process involving dysregulations in cell adhesion, proliferation, survival and migration. Breast epithelial cells contain several multi-protein adhesion complexes at two principal sites, between neighbouring cells and between cells and their extracellular matrix. Adhesion proteins regulate a variety of cellular functions, and dysregulation of cellular adhesion has been implicated in the events that accompany cancer initiation and progression. Proteins of the intercellular tight junction have been found to be de-regulated in several human cancers including breast, and have recently been suggested as promising targets for cancer therapy. This thesis is focused on exploring the contribution of one tight junction protein, junctional adhesion molecule-A (JAM-A) to breast cancer progression. In this thesis we used two isogenic breast cancer cell line models, HMT-3522 and Hs578T, both of which have "non-tumorigenic" and "tumorigenic" variants. We observed that tumorigenic HMT- 3522 T4-2 cells had tighter junctions compared to non- tumorigenic cells, and that the tumorigenic variant of Hs578T cells expressed a higher level of JAM-A. JAM-A expression was also higher in primary breast cultures from tumour relative to non-tumour samples, and highest in aggressive high grade turnours. Interestingly, we detected high levels of soluble JAM-A in serum samples of breast cancer patients with benign disease compared to patients with invasive ductal carcinomas. Functional inhibition of JAM-A was found to decrease protein levels of JAM-A in both nontumorigenic and tumorigenic cells and to significantly reduce ceII migration. In 3-dimensional cultures mimicking the in vivo microenvironment, JAM-A inhibition was found to decrease cell number and 3-dimensional spheroid formation and, for the first time, to partially normalise the ahomalltumorigenic phenotype of invasive cells. Taken together, our study provides novel evidence suggesting that JAM-A may be involved in breast cancer progression and have potential as a biomarker of disease progression or as a therapeutic target.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

File Size

9 MB

Comments

A thesis submitted to the Royal College of Surgeons in Ireland for the degree of Doctor of Medicine from the National University of Ireland in 2011.

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