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Protein Trim62 may help to define role of p27 in breast cancer prognosis
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International Conference on Molecular Targets and Cancer Therapeutics
It is well known that levels of a protein called p27 are related to breast cancer outcomes, but less is known about the reasons behind this. Researchers at the Fred Hutchinson Cancer Research Center in Seattle have determined that another protein, called Trim62, regulates p27 and may be one key to understanding the relationship between p27 and breast cancer prognosis.
In tumor cells, the cell cycle inhibitor p27 is often decreased in the tumor cell’s nucleus, while retained or increased in the cytoplasm. When in the nucleus, p27 functions as a tumor suppressor by inhibiting cell proliferation. However, when in the cytoplasm, p27 promotes cell migration and may thereby increase the tumor’s potential to spread to other parts of the body. Thus, the location and distribution of p27 in the tumor cell may help indentify more aggressive tumors.
To this end, Claire M. Faltermeier and colleagues in the Hutchinson Center’s basic sciences division developed antibodies that could reliably detect cytoplasmic p27. They observed that HER-2–positive breast cancers usually have increased cytoplasmic p27.
“Although it has been established that cytoplasmic p27 could function as an oncogene, it has been difficult to determine which types of cancers have cytoplasmic p27 and its prognostic significance because of the lack of molecular tools to reliably detect cytoplasmic p27,” said Faltermeier, lead author and research assistant in the lab of Jim Roberts, MD, PhD, at the Hutchinson Center. “Now that antibodies have been developed to detect cytoplasmic p27, we can correlate cytoplasmic p27 to specific types of cancers and patient outcomes.”
Faltermeier and co-author Erik Eide, PhD, post-doctoral research fellow in Robert’s lab, also indentified a novel protein, Trim62, which not only regulates p27 stability but also its localization in HER-2–positive breast cancers. When Trim62 levels were knocked-down in HER-2–positive cancer cells, p27 that was in the cytoplasm moved to the nucleus and the cells stopped proliferating. Furthermore, they showed that when Trim62 levels were reduced, HER-2–positive cancer cells were more sensitive to the effects of lapatinib (Tykerb, GlaxoSmithKline) while increased levels of Trim62 had the opposite effect.
“Our research suggests that Trim62 is responsible for the misregulation of p27 in HER-2–positive breast cancer tumors,” Faltermeier said. “Because it regulates the stability and location of p27 in tumor cells, Trim62 could be a potential biomarker to predict patient response to anti-HER-2 therapeutics such as lapatinib.”
For more information:
- Faltermeier CM. #A64. Presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; Nov. 15-19, 2009; Boston.