Lani
11-20-2009, 11:18 AM
and sensitivity to it
Specifically for her2+ breast cancer
Protein Trim62 regulates p27, affecting HR+ breast cancer prognosis
[American Association for Cancer Research]
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 (FHCRC) 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 (the control center of the cell), while retained or increased in the cytoplasm (the area outside the nucleus). When in the nucleus, p27 functions as a tumor suppressor by inhibiting cell proliferation (growth and duplication). 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 breast cancers positive for a certain growth factor receptor, called HER2, usually have increased cytoplasmic p27.
"While 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, M.D., Ph.D., 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, Ph.D., 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 HER2 positive breast cancers. When Trim62 levels were reduced (knocked-down) in HER2 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, HER2 positive cancer cells were more sensitive to the effects of lapatinib (a HER2/EGFR inhibitor) while increased levels of Trim62 had the opposite effect.
"Our research suggests that Trim62 is responsible for the misregulation of p27 in HER2 positive breast cancer tumors," said Faltermeier. "Because it regulates the stability and location of p27 in tumor cells, Trim62 could be a potential biomarker to predict patient response to anti-HER2 therapeutics such as lapatinib."
ABSTRACT #A64: Mechanistic insights into the misregulation of p27 in HER2-positive breast cancers (PDF)
[American Association for Cancer Research]
Although it is often stated that low amounts of the cell cycle inhibitory protein p27 are predictive of a poor outcome in breast cancers, this is an oversimplifcation of the data. Typically, tumor cells exhibit decreased expression of p27 in the nucleus, while preserving or even increasing the pool of p27 in the cytoplasm.Whereas nuclear p27 is tumor suppressive by inhibiting cell proliferation, newer evidence suggests that cytoplasmic p27 has an oncogenic action: it interacts with the GTPase RhoA to promote cellular migration and motility. Thus, cytoplasmic p27 may be an indicator of tumor cell invasiveness and metastatic potential. Understanding the mechanism of p27 mislocalization in breast cancers may offer insight into pathways of oncogenic transformation, and provide new markers for predicting clinical responses to specific therapies. Toward this goal, we developed antibodies that reliably detect cytoplasmic p27, and also identified a subset of breast cancers positive for the growth factor receptor HER2 that exhibited increased amounts of cytoplasmic p27. In parallel experiments we discovered an E3 ubiquitin ligase, Trim62 that regulates p27 stability, and found that it is overexpressed in HER2+ breast cancers. siRNA knock down of Trim62 in HER2+ breast cancer cell lines not only induced cell cycle arrest but also caused p27 to relocate entirely to the nucleus.We compared knock down of Trim62 to that of the well-characterized p27 regulator, the F box protein Skp2. Unlike Trim62, Skp2 inhibition had no detectable effect on p27 in these cells. As pharmacological inhibition of HER2 has also been shown to increase nuclear p27 protein levels, we investigated the role of Trim62 in modulating the response of breast cancer cells to anti- HER2 therapeutics. Like Trim62 siRNA, the HER2/EGFR inhibitor, Lapatinib increased p27 amounts, and this increase in p27 was located exclusively in the nucleus. Furthermore, we showed that knockdown of Trim62 increased cellular sensitivity to Lapatinib. Overexpression of Trim62 had the opposite effect. Collectively, our results suggest Trim62 underlies the misregulation of p27 in HER2+ breast cancer cell lines. By modulating p27 expression and cellular localization, Trim62 may mediate the antiproliferative effect of HER2 antagonists in breast cancer cells. Moreover, Trim62 could be a potential biomarker to predict biological response of breast cancer cells to anti-HER2 therapeutics such as Lapatinib.
Specifically for her2+ breast cancer
Protein Trim62 regulates p27, affecting HR+ breast cancer prognosis
[American Association for Cancer Research]
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 (FHCRC) 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 (the control center of the cell), while retained or increased in the cytoplasm (the area outside the nucleus). When in the nucleus, p27 functions as a tumor suppressor by inhibiting cell proliferation (growth and duplication). 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 breast cancers positive for a certain growth factor receptor, called HER2, usually have increased cytoplasmic p27.
"While 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, M.D., Ph.D., 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, Ph.D., 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 HER2 positive breast cancers. When Trim62 levels were reduced (knocked-down) in HER2 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, HER2 positive cancer cells were more sensitive to the effects of lapatinib (a HER2/EGFR inhibitor) while increased levels of Trim62 had the opposite effect.
"Our research suggests that Trim62 is responsible for the misregulation of p27 in HER2 positive breast cancer tumors," said Faltermeier. "Because it regulates the stability and location of p27 in tumor cells, Trim62 could be a potential biomarker to predict patient response to anti-HER2 therapeutics such as lapatinib."
ABSTRACT #A64: Mechanistic insights into the misregulation of p27 in HER2-positive breast cancers (PDF)
[American Association for Cancer Research]
Although it is often stated that low amounts of the cell cycle inhibitory protein p27 are predictive of a poor outcome in breast cancers, this is an oversimplifcation of the data. Typically, tumor cells exhibit decreased expression of p27 in the nucleus, while preserving or even increasing the pool of p27 in the cytoplasm.Whereas nuclear p27 is tumor suppressive by inhibiting cell proliferation, newer evidence suggests that cytoplasmic p27 has an oncogenic action: it interacts with the GTPase RhoA to promote cellular migration and motility. Thus, cytoplasmic p27 may be an indicator of tumor cell invasiveness and metastatic potential. Understanding the mechanism of p27 mislocalization in breast cancers may offer insight into pathways of oncogenic transformation, and provide new markers for predicting clinical responses to specific therapies. Toward this goal, we developed antibodies that reliably detect cytoplasmic p27, and also identified a subset of breast cancers positive for the growth factor receptor HER2 that exhibited increased amounts of cytoplasmic p27. In parallel experiments we discovered an E3 ubiquitin ligase, Trim62 that regulates p27 stability, and found that it is overexpressed in HER2+ breast cancers. siRNA knock down of Trim62 in HER2+ breast cancer cell lines not only induced cell cycle arrest but also caused p27 to relocate entirely to the nucleus.We compared knock down of Trim62 to that of the well-characterized p27 regulator, the F box protein Skp2. Unlike Trim62, Skp2 inhibition had no detectable effect on p27 in these cells. As pharmacological inhibition of HER2 has also been shown to increase nuclear p27 protein levels, we investigated the role of Trim62 in modulating the response of breast cancer cells to anti- HER2 therapeutics. Like Trim62 siRNA, the HER2/EGFR inhibitor, Lapatinib increased p27 amounts, and this increase in p27 was located exclusively in the nucleus. Furthermore, we showed that knockdown of Trim62 increased cellular sensitivity to Lapatinib. Overexpression of Trim62 had the opposite effect. Collectively, our results suggest Trim62 underlies the misregulation of p27 in HER2+ breast cancer cell lines. By modulating p27 expression and cellular localization, Trim62 may mediate the antiproliferative effect of HER2 antagonists in breast cancer cells. Moreover, Trim62 could be a potential biomarker to predict biological response of breast cancer cells to anti-HER2 therapeutics such as Lapatinib.