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Full NameDr Sanjeev Gupta
PATHOLOGY
National University of Ireland Galway
Webpage:nuigalway.ie
Email Address:Email hidden; Javascript is required.
- 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.