Identification of tumor suppressor genes and oncogenes that are somatically altered and that contribute to an aggressive tumor genotype and chemoresistance

The TP53 gene is mutated in 20-30% of primary breast carcinomas and 50-75% in ovarian carcinomas. We have previously shown that breast cancer patients with mutations affecting specific regions of the protein have a significantly shorter survival indicating that they have a more aggressive tumor, and respond poorly to DNA damaging drugs like doxorubicin or FUMI. Whether the different mutations found have different effect on tumor aggressiveness and whether polymorphisms found in this gene effect the oncogenic potential of a mutation is explored. This is analyzed using the yeast functional assay expressing the different TP53 mutants on different allelic background and analyzed for transactivation of different genes like p21, bax and PIG3.

Further studies on both breast and ovarian cancer, coupling the mutation to the genetic background they reside on (i.e. TP53 haplotypes) and correlating to expression profile, tumor behaviour and clinical outcome are the basis for the newly granted EU project on “Mutant TP53 as target for improved Cancer Treatment“.

Alternative genes involved in the same pathway as TP53, are investigated for mutations. These includes the ATM, CHK1,CHK2, CDC25, PIG3.

Persons involved in this project are Post docs Therese Sørlie and Åslaug Helland, PhD students: Anita Langerød and Pedro Kringen, Anna Bergamaschi, and Yun Wang (on the ovarian carcinomas), and medical Technologists Hilde Johnsen and Eldri Undlien Due.

From the expression studies and genome wide copy number analyses a number of other candidate genes differentially expressed are being explored for mutations. These includes GATA3, HNF3 and BUB1, MAD, MAD4, RERG and others. This is performed in collaboration with Stephen Cannock at NCI and Chuck Perou at UNC.