Breast Cancer

Breast cancer is the most frequent cancer and cause of mortality related to cancer among women (Parkin, 2005). About 15% of women will be diagnosed with breast cancer during their lifetime.

Breast cancer is commonly oestrogen dependent. This steroid hormone acts by activating its cellular receptor, the oestrogen receptor, which in turn modulates the expression of hundreds of genes. Some of these genes are involved in cell proliferation that is an important step in tumour formation.

Therefore, a major treatment of breast cancer aims at reducing oestrogen receptor activity in breast, either by suppressing oestrogen levels (inhibition of oestrogen production using aromatase inhibitors) or by using oestrogen receptor antagonists (anti-oestrogens such as tamoxifen), which compete with oestrogen for binding their receptor.

Tamoxifen has long been the drug of choice for endocrine therapy and more recently for the prevention of breast cancer (Osborne, 1998). However, although tamoxifen treatment is initially beneficial in a significant proportion of patients, some patients eventually acquire resistance to tamoxifen treatment, leading to tumour progression and death (Osborne, 1998). In addition, many tumours lose the expression of the oestrogen receptor during the progression of the disease and, in this case, endocrine therapy is not possible anymore.

Dividing Breast Cancer Cells; Steve Gschmeissner / SCIENCE PHOTO LIBRARY

In this context, it is important to underline that cancer cells are not fixed in a particular phenotype but are rather able to evolve within their environment. During tumour progression, cancer cells develop various behaviours: after a proliferation step, some tumour cells favour the vascularisation (angiogenesis) of the tumour while some cells are able to leave the tumour, migrate within blood vessels and colonise other tissues. These behaviours of cancer cells lead to the formation of metastases that dramatically increase the risk of death. To date, most of the treatments at these later stages are inefficient. In addition and as already mentioned, cancer cells are able to become resistant to various treatments.

To better understand how cancer cells evolve, that is how they are able to develop various behaviours, to adapt to changing environments and to become resistant to treatments, we made the hypothesis that these cells generate new gene products through alternative splicing.

Transcriptome analyses have revealed that more than 50% of human genes encode distinct protein isoforms by alternative splicing of their pre-mRNAs (Stamm, 2005). Consequently, alternative splicing is a major mechanism generating human proteome diversity. In addition, isoform-selective gene expression is thought to be important for cellular phenotype because splice isoforms often have distinct or opposite functions (Mercatante and Kole, 2000; Stamm, 2005).

In cancer cells, not only there are many examples of splice variant deregulation but cancer cells also express “aberrant” splicing products that are not found in normal cells (Wang, 2003). Therefore, we believe that alternative splicing might be a way for cancer cells to increase their protein repertoire, thereby enabling them to evolve.

A better understanding of how cancer cells use alternative splicing to evolve will generate new therapeutic strategies to block tumour progression. In this context, our goal is to develop strategies targeting alternative splicing regulation in order to force tumour cells to produce spliced variants having anti-tumour properties.

Parkin DM et al., 2005. CA Cancer J Clin 55(2): 74-108.

Mercatante, D. and R. Kole (2000). Pharmacol Ther 85(3): p. 237-43.

Osborne CK. (1998) N Engl J Med 339(22):1609-18

Stamm S. et al., 2005. Gene 344:1-20.