Breast cancer is the most common malignant tumour diagnosed in women in Ireland, with more than 2,800 new cases each year (National Cancer Registry Ireland). Although survival from breast cancer has improved greatly (currently 82% of women diagnosed with breast cancer are surviving at least 5 years), it is still the second most common cause of cancer-related death in women (after lung cancer).
Similar to blood cancers, breast cancers can be divided into many different sub-types, depending on the characteristics of the tumour. The presence or absence of the HER2 protein and the hormone receptors for oestrogen and progesterone on the surface of the cell is one way in which breast cancer subtypes are defined. Cancers expressing high levels of HER2/hormone receptors are often driven by these pathways and so can be used to target that cancer using Herceptin or relevant hormone treatments. Triple negative breast cancer (TNBC) on the other hand, does not express high levels of any of these drivers of cancer, so no targeted treatments are available. This is one of the most aggressive breast cancer subtypes, with high rates of tumour recurrence and poor overall survival.
Many of our research teams are applying their knowledge of cell death mechanisms to the investigation of better diagnostics, prognostics and therapies for breast cancer, in particular triple negative breast cancer.
Dr Sharon Glynn, whose interest in breast cancer research was first established during her Cancer Prevention Fellowship at the National Cancer Institute in the USA, has continued her investigations of inflammation in hormone-independent breast cancer since moving to Galway in 2010. Her work focuses on nitric oxide synthase (NOS2), which drives inflammation and wound-healing responses. Inflammation has been proposed as a contributing causal factor in many cancers, and cancer has been likened to a ‘wound that never heals’ due to the similarities between the processes involved in wound-healing and the growth and development of tumour stroma.
One of the most significant discoveries made by Dr Glynn to date showed that NOS2 predicted poor outcome in patients diagnosed with oestrogen receptor (ER)-negative breast cancer (Glynn et al., J Clinical Invest. 2010). This was a much stronger predictor than current clinical pathological predictors of outcome. Also, using microarray analysis, she demonstrated that NOS2-overexpressing tumours had stem cell-like signatures, increased inflammation signalling and basal-like features. These findings were reproducible in cell line models of breast cancer.
Similar to NOS2, Glynn also showed that COX2 overexpression is associated with ER-negative disease (Glynn et al., BMC Cancer, 2010). This inflammation-driven pathway identified in ER-negative tumours provides a potential rationale for the aggressiveness of hormone-independent breast cancers.
One mechanism by which chemotherapy works is by producing ‘free radicals’ in a mechanism that is similar to radiation, whereby the free radicals bombard and destroy the tumour. Anti-oxidants are molecules that ‘mop-up’ free radicals, preventing them from causing damage to the cell. Dr Glynn discovered that a genetic alteration, known as a polymorphism, in an anti-oxidant gene called MnSOD, alters its anti-oxidant activity, allowing MnSOD to ‘mop-up’ the free radicals before they can destroy the tumour cells (Glynn et al., Clin Cancer Res, 2009). This polymorphism in the MnSOD gene predicted a poor response to chemotherapy in breast cancer patients. This knowledge could allow clinicians to personalise a patient’s treatment based on their genetic profile, choosing the right chemotherapy for them or avoiding chemotherapy if their genetic profile shows that they are unlikely to benefit. This unique discovery was granted a US patent in 2010 (US Patent 7,985,561).
Dr Adrienne Gorman’s work on triple negative breast cancer has implicated a new role for the pro-survival signalling molecule, nerve growth factor (NGF) as a mediator of chemoresistance in this disease (Chakravarthy, Mnich, Gorman, Biochem Biophys Res Commun, 2016). Triple negative breast cancer is reported to secrete nerve growth factor and its receptors, leading to a pro-survival signalling loop. Dr Gorman’s group showed that when TNBC cells were exposed to NGF, this increased the levels of the NGF receptor and caused a decrease in the sensitivity of these cancer cells to cell death by apoptosis induction. Furthermore, blocking the NGF receptor increased the sensitivity of TNBC cells to drug-induced apoptosis. Data from patient samples also supports a role for NGF-mediated upregulation of NGF receptor as a mechanism for chemoresistance in TNBC. This study provides a rationale for NGF as a potential therapeutic target for TNBC.
Ongoing research at the Apoptosis Research Centre in the area of Breast Cancers includes:
Dr Sharon Glynn:
- Dr Glynn’s group’s current area of interest in breast cancer is to further investigate NOS2 in triple negative breast cancer and also to investigate potential links with HERV-K and investigating the functions of HERV-K proteins and their mRNAs.
- Current studies are investigating how inflammation pathways (mediated by NOS2 and COX2) are driving increased metastasis in triple negative breast cancer
Dr Susan Logue:
- Research interests include the role of stress response pathways, such as the unfolded protein response, in driving progression and post-therapy responses such as chemotherapy resistance and tumour initiating stem cell expansion in breast cancer.