Funded PhD Position:
Title: Breast & ovarian cancer studies in Xenopus oocytes and embryos.
PI: (opens in a new window)Associate Professor Carmel Hensey
Epidermal growth factor receptor overexpression in breast and ovarian cancer has been well characterised, especially HER1/EGFR and HER2/ERB2 with HER2 being the target of the highly successful monoclonal antibody therapy, trastuzumab (Herceptin®). These EGFs are membrane receptors that heterodimerize upon ligand binding and regulate many cellular processes such as cell cycle, cell proliferation and gene expression (Bonello et al, 2018).
HER4 is the least understood receptor of the HER family. It is processed into a soluble intracellular domain, which can disperse to the cell cytoplasm or nucleus. In breast cancer, nuclear localization of the intracellular domain in combination with estrogen expression predicted worse clinical outcomes compared to membrane HER4 and estrogen (Jones FE 2008). There are conflicting views about the expression of HER4 in ovarian cancer with some studies suggesting an increased expression of HER4 in malignant tissues compared to normal tissues (Steffensen et al., 2008). Although the implication of HER4 expression in ovarian cancer is unclear, a possible correlation between HER4 expression and resistance to chemotherapy has been reported (Gilmour at al, 2004).
Xenopus laevis (African clawed frog) provides a unique in vitro and in vivo model for cancer research. Oocyte and early embryo extract assays can model aspects of cell cycle related cell signalling, including meiosis, mitosis, DNA replication, DNA damage and DNA repair mechanisms (Hardwick et al, 2018; Robertson et al, 1999; O’Shea et al, 2013; O’Shea et al, 2019; Mann et al., 2022). ErbB receptors (XEGFR, XErB2, XErB3, XErB4) are expressed in Xenopus oocytes and early embryos and were shown to regulate cell proliferation and patterning (Nie and Chang, 2006).
This research project will focus on understanding the regulation of XErB4 in oocytes, oocyte extracts and early embryos. In particular we want to establish whether XErB4 regulates/interacts with the cell cycle machinery or the DNA damage/repair pathways and p53, BRCA1 & BRCA2. Relevant findings will be extended to analysis of clinical breast and ovarian cancer samples and tumour data.
This research has the potential to impact health and well being. While there are many excellent drugs targeting EGFR signalling in breast and ovarian cancer, in some cases they don't work and in other cases resistance is eventually established. An increased understanding of these receptors, particularly the roles of the lesser studied ones such as HER4, may open new routes to therapy.
Bonello M, Sims AH, Langdon SP. Human epidermal growth factor receptor targeted inhibitors for the treatment of ovarian cancer. Cancer Biol Med. 2018 Nov;15(4):375-388. doi: 10.20892/j.issn.2095-3941.2018.0062. PMID: 30766749; PMCID: PMC6372909.
Gilmour LM, Macleod KG, McCaig A, Gullick WJ, Smyth JF, Langdon SP. Expression of erbB-4/HER-4 growth factor receptor isoforms in ovarian cancer. Cancer Res. 2001 Mar 1;61(5):2169-76. PMID: 11280782.
Hardwick LJA, Philpott A. Xenopus Models of Cancer: Expanding the Oncologist's Toolbox. Front Physiol. 2018 Nov 27;9:1660. doi: 10.3389/fphys.2018.01660. PMID: 30538639; PMCID: PMC6277521.
Requirements:Applicants should have a minimum of upper 2nd class honours
degree (or equivalent) in Pharmacology, Biochemistry, Cell Biology or related biomedical science
discipline.
Conditions:
- September/October 2023 start date.
- Full EU fees + €20,000 per annum stipend over four years; EU/UK applicants only
- The student will be enrolled in a Structured PhD programme, associated with the School.
- Each student is required to demonstrate in appropriate laboratory practicals as part of their funded scholarship. Demonstrating hours and lab practicals are detailed and assigned by the SBBS Demonstrating Committee (maximum hours: 288 per annum) .
- The student and supervisor are required to submit an application for an IRC Postgraduate Scholarship in the first year of their SBBS-funded research scholarship
Apply: Applications should contain a 1-page cover letter outlining your interest and suitability for the
position, a detailed CV and contact information for 2 referees. Applications should be received by
email to carmel.hensey@ucd.ie, no later than July 30th 2023. Informal inquiries may be made by
email prior to the application deadline.