Role of inflammation in the propagation of breast cancer stem cells and resistance to endocrine therapy

Breast cancer is one of the most common causes of cancer-related deaths in women. Anti-hormonal therapy has improved the prognosis of ER-positive breast cancers, but late recurrences are still very frequent. The majority of recurrences are metastases that lead to the patient’s premature death. Therefore, new approaches are necessary to prevent recurrence and metastasis, during or after endocrine-therapy.

Hypothesis. Endocrine resistance is related to the emergence of ER-negative cancer stem cells. We hypothesise that the cancer stem cell phenotype could be modulated or reversed by inflammatory mediators, thereby conferring sensitivity to endocrine-therapy.

Objectives:

1) To determine if inflammatory mediators promote or inhibit the growth of ER-negative cancer stem cells.
2) To investigate if inflammatory mediators can reverse resistance to endocrine-therapy.
3) To generate new predictive biomarkers of the response to hormonal therapy, using inflammatory cell models, via Omics analysis.

Methods: ER-positive breast cancer cell lines (MCF7 and T47D) will be engineered to overexpress inflammatory mediators (TNF-alpha or Interferon-alpha, beta, gamma). Then, these cells will be assayed for cancer stem cell activity: 1) using the mammosphere assay; 2) by FACS analysis using CD44/CD24 as molecular markers of stemness. These cell lines will also be assayed for sensitivity to growth in increasing concentration of tamoxifen. Tamoxifen-resistant MCF7 cells (TAM-R) will be used as positive control for hormonal-resistance.

Importantly, our preliminary results indicate that breast cancer cells overexpressing TNF-alpha or Interferons have dramatically reduced ability to form mammospheres, indicating a significant reduction in stemness.

Since nearly half of all ER-positive patients become resistant to hormonal therapy, this project will provide a new therapeutic strategy for preventing treatment failure, tumour recurrence and metastasis.

The project and training will exploit Omics technologies for the biomolecular characterization of the endocrine resistance, cancer stem cell and the pro-inflammatory phenotypes.

For the development of cross-cutting skills, the PhD studentship will include the use of biological and computational approaches to manage and analyse the large datasets generated during Omics analysis of specific cellular models. The succcessful candidate will be exposed to the interpretation of the outputs from various ‘Omics’ based approaches.

This 4-year full-time studentship forms one of our PhD opportunities within the MRC Doctoral Training Partnership (MRC DTP) scheme. Funding provides full support for tuition fees, annual tax-free stipend at Research Council UK rates (currently £13, 863) and conference/travel allowance. The project is due to commence October 2015 and is open to UK/EU nationals only due to the nature of the funding.

Applicants should hold (or expect to obtain) a minimum upper-second honours degree (or equivalent) in oncology, cell biology, bioinformatics, genetics, pathology or a related medical/health science. A Masters qualification in a similar area would be an advantage.

Please direct applications in the following format to Dr Federica Sotgia ([Email Address Removed]):

• Academic CV
• Official academic transcripts
• Contact details for two suitable referees
• A personal statement (750 words maximum) outlining your suitability for the study, what you hope to achieve from the PhD and your research experience to date.

Any enquiries relating to the project and/or suitability should be directed to Dr Sotgia. Applications are invited up to and including 26 November 2014.

Further details on the MRC DTP scheme, shortlisting/interview process and additional PhD project opportunities can be found on our website: www.mhs.manchester.ac.uk/mrcdtp

http://www.cancer.manchester.ac.uk/staff/sotgia

www.mhs.manchester.ac.uk/mrcdtp
http://www.mhs.manchester.ac.uk/postgraduate/mhs-graduate-school/