Ludwig Institute for Cancer Research

Research Programs

Cancer Genetics

Gene Discovery & Characterization

Identifying and characterizing genes affected by cancer may not only help us to understand how and why the disease happens, but may also lead to better prognostic and diagnostic tests and therapy targets.

Introduction

Some genes are categorized according to their function in the etiology of cancer. Genes in which mutations promote cancer onset are ‘oncogenes’ - the mutation activates the gene product to cause cell growth, proliferation or differentiation - or ‘tumor suppressor genes’ - the mutation nullifies the gene product to resist cell cycle or control or apoptosis. The characterization of oncogenes and tumor suppressor genes not only increases our understanding of cancer biology, but may also provide markers for diagnosis and treatment, for example amplification of the erbB-2/HER-2 gene is an predictor of clinical response to the targeted antibody, Herceptin®. Some genes, while not involved in the cancer onset, accumulate mutations as cancer progresses, and these may also provide diagnostic and prognostic information and therapy targets.

ASPP/iASPP

Transcription factor p53 is a tumor suppressor gene and one of the most frequently mutated genes in human cancers. Normal, or wild-type, p53 induces cell cycle arrest and apoptosis, but mutated p53 ‘protects’ the transformed cell from apoptosis allowing it to grow and proliferate uncontrollably. However, despite the tumor-suppressor function of p53 being lost in most (perhaps all) tumors, not all have p53 mutations. LICR investigators have been studying p53-interacting proteins to identify those that inhibit p53’s function when the gene itself is not mutated. While the biology behind p53’s tumor-suppressor function is fascinating, there are also potential patient-oriented benefits to understanding and controlling p53 induction. Inducing p53 activity in cancer cells would theoretically be of therapeutic benefit in many cancers, either by inducing apoptosis or rendering the cells more sensitive to chemotherapies.

LICR investigators in London initially identified the ASPP1 and ASPP2 proteins as being able to specifically enhance p53’s apoptotic function by stimulating the transcription factor’s DNA binding and activation on the promoters of pro-apoptotic genes in vivo. ASPP mRNA levels were also shown to be down-regulated (lowered) in breast cancer cell lines, suggesting that loss of ASPP may be a mechanism through which the function of wild-type p53 is lost ⁽¹⁾. Subsequently, the team found a third member of the ASPP family, iASPP, which inhibits p53 function. The iASPP protein was shown to be up-regulated (high) in breast cancers and confer increased resistance to apoptosis induced by the chemotherapy, cisplatin⁽²⁾. Together, these studies indicate that the inhibition of iASPP is a promising target for future therapies in cancers that have wild-type p53, particularly for breast cancer⁽³⁾.

The UCL Branch team is continuing to characterize the ASPP family by examining its interaction with other proteins related to p53-mediated apoptosis. For example, they showed that ASPP1 and ASPP2 are regulated by the E2F family of transcription factors, which regulates the expression of several proteins involved in cell cycle control, DNA replication and apoptosis ⁽⁴⁾. The group also found that other proteins, Mdm2 and mdmx, prevent ASPP1 and ASPP2 from stimulating p53’s apoptotic function by binding and inhibiting the transcriptional activity of p53⁽⁵⁾.

Identification of Potential Immunotherapy Targets

Investigators from the Lausanne and New York Branches led a collaboration of academic and commercial groups that used massively-parallel signature sequencing (MPSS) technology (see also Gene Expression Profiling) to identify 20 genes that encode putative cancer-testis (CT) antigens⁽⁶⁾. CT genes are genes expressed in normal germ-line cells and in cancer cells, while CT antigens are CT gene products recognized by the immune system. It was shown that a substantial proportion of CT or CT-like genes are found on the X-chromosome, and a new gene family of distinctive X-linked CT antigens was identified. The data were made publicly-available at http://mpss.licr.org.

References

1. Samuels-Lev Y., O'Connor D.J., Bergamaschi D., Trigiante G., Hsieh J.K., Zhong S., Campargue I., Naumovski L., Crook T., and Lu X. ASPP proteins specifically stimulate the apoptotic function of p53. Mol.Cell (2001) 8(4):781-794.
2. Bergamaschi D., Samuels Y., O'Neil N.J., Trigiante G., Crook T., Hsieh J.K., O'Connor D.J., Zhong S., Campargue I., Tomlinson M.L., Kuwabara P.E., and Lu X. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nat.Genet. (2003.)
3. Trigiante G. and Lu X. ASPPs and cancer. Nat.Rev.Cancer (2006) 6(3):217-226.[PM:16498444]
4. Fogal V., Kartasheva N.N., Trigiante G., Llanos S., Yap D., Vousden K.H., and Lu X. ASPP1 and ASPP2 are new transcriptional targets of E2F. Cell Death.Differ. (2005) 12(4):369-376.
5. Bergamaschi D., Samuels Y., Zhong S., and Lu X. Mdm2 and mdmX prevent ASPP1 and ASPP2 from stimulating p53 without targeting p53 for degradation. Oncogene (2005) 24(23):3836-3841.
6. Chen Y.T., Scanlan M.J., Venditti C.A., Chua R., Theiler G., Stevenson B.J., Iseli C., Gure A.O., Vasicek T., Strausberg R.L., Jongeneel C.V., Old L.J., and Simpson A.J. Identification of cancer/testis-antigen genes by massively parallel signature sequencing. Proc Natl.Acad.Sci.U.S.A. (2005) 102(22):7940-7945