A new promising enzyme target for a specific type of breast cancer, Brk, has been identified in research published on August 21, 2008 in the Proceedings of the National Academy of Sciences (PNAS.)

In a specific subset of breast cancer patients, the tumor cells produce high levels of the protein ErbB2 (also called HER2) which pushes the cells to proliferate without limit, a characteristic common of all cancers. Approximately one in four patients are in this group, and their clinical prognoses are considerably worse than other patients. While Herceptin and Lapatinib, concomitantly administered with other chemotherapic agents, have improved the prognosis for many of these patients, there is significant potential for development in this area. In particular, they are able to suppress ErbB2, but are not effective against all tumors that secrete it. Additionally, when patients’ tumors do respond, they usually become resistant over time.

According to the authors of this study, led by Professor Senthil Muthuswamy, Ph.D of the Cold Spring Harbor Laboratories, this suggested that another element might factor into the progression of these tumors. “The limited success of existing therapy suggested to us that factors besides ErbB2, or proteins that collude with ErbB2, might nullify the effects of Herceptin and Lapatinib,” explained Dr. Muthuswamy.

ErbB2 is a type of molecule known as a receptor tyrosine kinases. Implicated in many cancers, these molecules reside on the surface of the cell and detect cues in the surrounding environment which signal the cells to proliferate. In breast cancers, this over-production or ErbB2 in breast cancers are due to a gene mutation resulting in multiple copies of the gene.

Brk is another protein that undergoes this sort of amplification due to multiple copies of its gene in the genome. This study focused on the potential link with Brk, which was previously shown to be over-produced in many types of cancers, including two-thirds of all breast cancers. By analyzing the genomes of several breast cancer patients helped showed an association between ErbB2 and Brk. To do this, they forced the production of both agents in the same cells, and noting the way they worked together, to see if they were over-produced in tandem.

The team examined tissue from more than two hundred patients for variations in the genome that could lead to multiple copies of both genes. In these samples, both proteins were amplified abnormally. Re-analyzing for the proteins themselves, rather than the genes, also indicated that the proteins were also over-expressed and thus in higher concentrations in the patients’ cells. This indicates that both might play an important role in the development of this type of cancer, and thus should both be targetted. “Our results might explain why the strategy of using ErbB2 inhibitors alone to treat breast cancers has fallen short,” said Dr. Muthuswamy. “These findings may also suggest a way to treat patients with advanced ErbB2-positive tumors and those who’ve developed resistance to ErbB2 inhibitors — an idea that we’re eager to test.”

In further experimentation, it became clear to the team that Brk was not able, in isolation, to induce cancerous proilferation, and instead enhanced the proliferation of cells also expressing ErbB2 by accelerating their entrance into the cell cycle. According to Dr. Muthuswamy, it may be useful to think of these proteins as factors in driving a car: “If ErbB2 is the accelerator that makes the car move, Brk helps shift the gear to gain more speed.”

Thus, Brk helps these tumors become virulent. Additionally, the team was able to implicate Brk in the drug-resistant properties of some of these tumors. This indicates, once again, that both must be targeted in future therapies. According to Muthuswamy: “We might need to hit ErbB2-expressing cancers with drugs against both ErbB2 and Brk.”

Brk might also be targeted in isolation. The scientists believe this to be a reasonable strategy because Brk influence appears to be specific to these cancer cells. “Brk does not promote the proliferation of normal cells, and its expression in normal tissues is restricted to non-proliferating cells.” Thus, many side effects that could be caused by other drugs, which target less specific chemicals, or are in higher levels in the cells.

Finally, Brk might have use in dianosing breast cancer. “We also think that Brk would be an ideal clinical marker than could be used to provide both a diagnosis and prognosis for breast cancer,” states Dr. Muthuswamy.

Brk is coamplified with ErbB2 to promote proliferation in breast cancer
Bin Xiang, Kiranam Chatti, Haoqun Qiu, B. Lakshmi, Alexander Krasnitz, Jim Hicks, Min Yu, W. Todd Miller, and Senthil K. Muthuswamy.
Proceedings of the National Academy of Sciences, August 21, 2008
doi: 10.1073/pnas.0805009105
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About Cold Spring Harbor Labs:

CSHL is a private, non-profit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding and ability to diagnose and treat cancers, neurological diseases, and other causes of human suffering. For more information, please visit http://www.cshl.edu.

Written by Anna Sophia McKenney