C is for Cancer and Colin Collins

Cancer cells often possess many more genetic abnormalities than are absolutely necessary for their survival, progression and metastasis. Upon close scrutiny, the genetic fingerprints of a tumor may differ markedly not only from the genetic fingerprints seen in normal human cells, but also from those found in another individual with the same type of tumor.

The challenge for cancer researchers: first, to identify which changes in the genetic program are common and important to tumors and second, to develop molecular markers to better classify tumors, select appropriate therapies, and design clinical trials. Ultimately, some of the genetic changes identified should lead to gene targets and new treatments.

After nearly a decade of sleuthing, UCSF Comprehensive Cancer Center molecular geneticist Colin Collins has identified such a target — a previously unknown and unsuspected gene, named ZNF217. In many breast tumors, there are too many copies of the ZNF217 gene, which leads to too much production of the ZNF217 protein.

This gene "amplification" is associated with a reduced likelihood of surviving after surgery because the breast cancer eventually recurs. In addition, Collins has discovered that the insertion and activation of ZNF217 genes in normal mammary cells growing in culture can cause them to become immortal — basically, they ignore signals telling them to remain in a non-proliferating state. Immortalization is thought to be a key cellular event in the evolution of cancer.

Collins has found that ZNF217 might in some cases be responsible when tumors become resistant to a chemotherapy drug, doxorubicin, commonly used to treat breast cancer.

Collins also determined that cancer cells that overproduce the ZNF217 protein acquire greater resistance to the drug than cancer cells making normal amounts of the protein. He now is developing molecular strategies for blocking ZNF217 function and increasing the effectiveness of anti-cancer therapies such as doxorubicin.

In related work, Collins and computer scientist Stanislav Volik recently developed a new technique for rapidly identifying and cloning regions of DNA within the human genome that are amplified, deleted, turned around or moved out of place within tumor cells.

Using the technique, called end-sequence profiling (ESP), speeds up the identification of important genes such as ZNF217. This is because ESP makes it possible to link changes in gene activity and protein production with particular instances of genomic damage, such as specific amplifications, to clinical outcome.

by Jeffrey Norris