Supervisor View Full Details 2nd

• cancer/oncology

• Pathology

• Oncology

Breast cancer is the most common cancer in women both in the developed and less developed world. It is estimated that worldwide over 586,012 women died in 2016 due to breast cancer (Global Health Estimates, WHO 2016). Incidence rate of breast cancer in Ireland is 122 per 100,000 women per year. Mortality rate (deaths per 100,000 per year) for breast cancer in Ireland is 26.8, ranking first amongst most common invasive cancer deaths. Number of breast cancer related deaths in Ireland per year is 711, i.e. ~2 women dying per day (National cancer registry, Ireland).

Around 70% of breast cancers in women need one or both of the female hormones (estrogen and progesterone) to grow. To treat these 'hormone-dependent' cancers, patients receive drugs that either block the production of estrogen or directly target a receptor protein that senses estrogen in the cancer cells. The estrogen receptor-alpha (ESR1) continues to be an important target in luminal breast cancer. Whereas the currently used endocrine therapies (e.g. aromatase inhibitors, tamoxifen and fulvestrant) have had considerable success, the effectiveness of these therapies is limited by de novo and acquired resistance, and in the case of fulvestrant, poor pharmacokinetic properties.

Genomic alterations at the ESR1 locus is an established mechanism of acquired endocrine therapy resistance. Hotspot point mutations clustering in the ligand-binding domain of ESR1 have been found in up to 40% of treatment-refractory, metastatic ER-positive breast cancer patients. The two most prevalent ESR1 point mutations (Y537S and D538G) show ligand-independent transcriptional activity, and partial resistance to anti-estrogens. Patients with metastatic disease harbouring ESR1 point mutations are resistant to standard‐of‐care endocrine therapy. There is an urgent clinical need to identify new effective targeted therapies, in order to best treat ESR1 mutant-positive metastatic breast cancer.

We use a combination of molecular cell biology, transcriptomics, proteomics and gene expression profiling techniques to identify new therapeutic targets and inhibitors to overcome endocrine resistance in metastatic breast cancers having ESR1 mutations.

Several mechanisms have been suggested to explain the altered activity of the estrogen-signaling pathway, such as the presence of ER mutations, aberrant activity of co-activator proteins, constitutive activation of growth factor receptors, and activation of the UPR. XBP1, a key component of the UPR, belongs to the activated transcription factor (ATF) family of transcription factors. Both the unspliced (XBP1-U) and spliced (XBP1-S) mRNAs are translated into proteins, where XBP1-U generates a 37-kDa protein and XBP1-S generates a 50-kDa protein. Compared to XBP1-S, little is known about the functions of the XBP1-U protein. XBP1-U has been reported to function as a dominant negative factor of XBP1-S, enhance the degradation of transcription factors such as FoxO1 and p53, and enhance the activity of transcription factors such as NF-κB and ER.

Expression of XBP1 mRNA is increased upon estrogen stimulation where ER binds to the enhancer region of XBP1 gene, resulting in increased transcription at the XBP1 promoter. The expression of the XBP1-S protein is increased upon estrogen stimulation of ER-positive human breast cancer cell. XBP1-S expression is elevated in endocrine-resistant breast cancer cells, and overexpression of XBP1-S can confer estrogen independence and resistance to both tamoxifen and fulvestrant. Increased XBP1-S expression is associated with poor clinical outcomes in endocrine-treated breast cancers. XBP1-S induces the expression of NCOA3 via the XBP1-binding sites present in its promoter during conditions of the UPR and estrogen stimulation. NCOA3, a member of the p160 family of coactivators, is a direct target of XBP1-S. NCOA3 has been shown to promote the initiation of breast cancer in addition to development of resistance to anti-hormonal therapy.

This proposal will evaluate the functional interaction between XBP1 and gain-of-function mutants of ESR1 in ER-positive breast cancer.