Breast cancer: another target?
A potential target for breast cancer treatment has been found
LifeSciencesToday based on the materials of the University of Pennsylvania School of Medicine:
Penn Researchers Identify Potential Target for Breast Cancer TherapyOverexpression of surface ErbB receptors accompanies the growth of many types of breast tumors.
Medications, such as Herceptin, blocking the signals of these receptors, stop the progression of the tumor in some patients. However, not all tumors respond in this way, and some eventually become resistant to this drug. Various substances interfering with this metabolic pathway at its other stages can enhance the reaction of the patient's body, but little is known about these molecules yet.
Professor of the Department of Pharmacology at the University of Pennsylvania School of Medicine Marcelo Kazanets and his colleagues found that the P-Rex1 protein is important for the transmission of the ErbB receptor signal. Moreover, overexpression of P-Rex1 is observed in almost 60 percent of breast cancer cases, and compared to those tumors where P-Rex1 is not expressed, such tumors are more likely to metastasize.
Breast tissue with P-Rex1-positive cancer cells (inside the oval, colored brown).
P-Rex1 is expressed only in cancer cells.
(Photo: Marcelo G. Kazanietz, Penn Medicine)
"We have identified the target following the ErbB receptors, which is probably important for the proliferation of cancer cells, their migration and metastasis," Kazanets comments on the results of the study. "Understanding how this pathway works should allow us to find new drugs or therapeutic approaches."
The study (Identification of the Rac-GEF P-Rex1 as an Essential Mediator of ErbB Signaling in Breast Cancer) is published in the journal Molecular Cell and is announced on the cover of its December issue.
The ErbB receptor family is well known to oncologists. It includes the epidermal growth factor receptor (EGFR), also known as ErbB1, the ErbB2 receptor (or HER2/neu), which is the target of Herceptin, as well as the ErbB3 and ErbB4 receptors.
In earlier works, Kazanets and others have already suggested that these receptors can use small proteins of the Rac metabolic pathway to transmit their signal. To find out if this is the case, Kazanets and his colleagues studied human breast cancer cell lines and found that one of the proteins of the Rac pathway, namely P-Rex1, is overexpressed in many cancer cell lines. Scientists have also found that P-Rex1 is present in certain breast tumors, especially those that express the Her2/neu receptor or the estrogen receptor and belong to the luminal (related to the lumen or cavity of the tubular organ – VM) subtype.
"We found that about two-thirds of the patients had very high levels of P–Rex1 expression in tumor cells in the lymph nodes," explains Kazanets. "There is probably a correlation between the expression of P-Rex1 and the ability of tumor cells to metastasize. Since P-Rex1 appears to be necessary for cell migration, which in turn is important for metastasis, we believe that blocking this pathway may reduce the risk of metastasis."
P-Rex1 may be an important component of a number of other pathways that contribute to the emergence and development of cancer. For example, the metabolic pathway of estrogen receptors is also based on P-Rex1, which means that targeted P-Rex1 inhibitors can improve the response to antiestrogenic drugs such as Tamoxifen.
Scientists have discovered that P-Rex1 is also used by another receptor, CXCR4, whose role in the development of cancer has recently been shown in many studies. Although it is involved in many tumor cell pathways, P-Rex1 is not expressed in most normal tissues. "This gives us a very good target. It's really cancer–specific," Kazanetz says. "Moreover, since P-Rex1 is expressed in certain subtypes of breast cancer, it could be an excellent prototype for future personalized medicine."
Preclinical data from other groups confirm the importance of the Rac pathway for cancer development. Small inhibitor molecules blocking proteins of the Rac pathway have a strong anticarcinogenic effect in model systems, although their use in the clinic still needs to be verified.
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27.12.2010