Breast Cancer Research – Prof Anna-Mart Engelbrecht
Prof Anna-Mart Engelbrecht
Title of the project
Therapeutic nutrient starvation and breast cancer: The effect of increased basal autophagy on doxorubicin treatment regimes.
Breast cancer is a major contributor to mortality in Western women. Anthracyclines, such as doxorubicin, are amongst the most valuable current treatments for breast cancer. Unfortunately, they are cytotoxic and often lead to cardiac failure. Solid tumours grow beyond the capacity of the blood vessels which leads to impaired delivery of oxygen and other nutrients. Autophagy is a process that becomes activated in nutrient poor conditions like these and has been proposed as a possible mechanism by which these cancer cells access valuable energy substrates. However, there remains some controversy regarding the status of autophagy as a tumour suppressor with many believing that it actually aids in tumour development. We believe that autophagy is active in these regions of tumours, acting as a survival mechanism, and that it is a dynamic process that prevents activation of apoptosis. However, if autophagy is forced to progress beyond a certain threshold then cell death becomes inevitable. We think that it is possible to manipulate autophagy in nutrient starved cancer cells by altering their microenvironment so that they contain fewer nutrients thereby causing autophagy to shift to an even more heightened state. Anticancer drugs need to move through the blood to gain access to tumour cells, but these tumours are usually poorly vascularised and cancer drugs such as doxorubicin fail to accumulate in lethal doses there. If autophagy is ‘sensitized’ using this proposed starvation therapy then potentially smaller drug doses would be needed to force cancer cells to commit to apoptosis earlier. This would shorten treatment regimes and increase effectiveness of these drugs. In our study we aim to do just that. First, by characterizing autophagy in a non-invasive and aggressive breast cancer cell lines in vitro, and then through caloric\protein restriction or autophagy induction using rapamycin in vivo.
Collectively, this part of the study provides very compelling evidence that cancer cells are able to transiently degrade cytoplasmic contents in order to tolerate acute amino acid starvation. Additionally, a potential mechanism is provided here, where preferential utilization of autophagy-produced fuel substrates, such as fatty acids, amino acids and glucose can buffer against decreases in ATP levels during acute amino acid deprivation.
The need for ATP does not always remain constant. Demand for substrates (assessed though demand for the universal free energy transmitter (ATP) of the cell) must be balanced with supply, and the increase in autophagy activity should not be separated from the processes that utilize its products. Currently, ignorance of the energy requirements of cancer cells and the possible role of autophagy necessitates continued research into this important area of oncology.
A review article is in preparation as well as a publication on the in vitro characterization of the model.
- Turn it on baby! But how much? Autophagy as a mechanism for sensitization of breast cancer cells to doxorubicin. Mark Thomas & Anna-Mart Engelbrecht, Cancer and Metabolism: Pathways to the Future 2010, Edinburgh, Scottland, Sept 2010.
- Autophagy as a mechanism for sensitization of breast cancer cells to doxorubicin. Mark Thomas & Anna-Mart Engelbrecht, PSSA, East London, 19-21 September 2010.