Cyclin E, A Potential Prognostic Marker in Breast Cancer

Abstract

PuMic reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining fS^adta heeded, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for Teducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and to the Office of Management and Budget,, Washington, DC 20503 AGENCY USE ONLY (Leave blank) REPORT DATE April 2000 REPORT TYPE AND DATES COVEREDFinal (1 Oct 94 -30 Mar 00) TITLE AND SUBTITLE Cyclin E, a Potential Prognostic Marker in Breast Cancer AUTHOR(S)Khandan Keyomarsi, Ph.D. Cyclin E, a G1 cyclin essential for S phase entry with a profound role in oncogenesis, is overexpressed and present in lower molecular weight (LMW) isoforms in breast cancer cells and tumor tissues. Alteration and overexpression of cyclin E are linked to poor patient outcome. We have established the use of cyclin E as a prognostic marker for breast cancer. Tumor specimens from 400 breast cancer patients were examined; changes of cyclin E expression were compared with seven other established tumor markers to patient outcome. Altered expression of cyclin E was observed in 91% of all breast cancers with poor prognosis where patients either died of breast cancer or were still with cancer at the last contact date. Similarly in 93% of all breast cancer patients where cyclin E was either not altered, or its alteration was minimal, patients had a favorable prognosis. We have also deciphered the mechanism of deregulation of cyclin E in breast cancer cells giving rise to the LMW forms of cyclin E. Our studies show that the LMW forms of cyclin E detected at a much higher level in tumor cells, arise from post-translational action of a protease. We have been able to generate and knockout the tumor specific LMW pattern of cyclin E by transient transfection of FLAG-tagged cyclin E constructs harboring these mutations in a breast cancer cell line. We have identified a novel elastase-type consensus sequence in the amino-terminus of cyclin E responsible for generating these tumor specific LMW isoforms. Lastly, studies using the drug Lovastatin demonstrated that this highly prescribed drug used to lower cholesterol levels is also capable of inducing all four cyclin dependent kinase inhibitors (CKIs) in a cell specific manner via cell cycle independent mechanism, through the inhibition of the proteasome. We have also devised a novel treatment strategy that protects normal cells against the toxic effects of chemotherapeutic agents, by reversibly arresting the normal cells in the G1 phase of the cell cycle. Where copyrighted material is quoted, permission has been obtained to use such material. FUNDING NUMBERS DAMD17-94-J-4081 PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)H...

Lack of cyclin E immunoreactivity in non-malignant breast and association with proliferation in breast cancer

“…In this study, expression of cyclin Ein more than 5% of tumour cells correlated significantly with poor tumour grade, which was in agreement with previous studies using immunoblotting (Keyomarsi et al, 1994;Nielsen et al, 1996). In addition, cyclin E expression was significantly associated with a high proliferation fraction, which had previously been demonstrated in the immunohistochemical study by Dutta et al (1995).…”

“…Overexpression of cyclin E has been observed in 10 out of 10 breast cancer cell lines and breast tissue using Western blotting techniques (Keyomarsi and Pardee, 1993;Keyomarsi et al, 1994;Nielsen et al, 1996). It has been suggested that deregulation of cyclin E may be a factor contributing to the malignant phenotype (Keyomarsi and Pardee, 1993;Keyomarsi et al, 1994;Dutta et al, 1995).…”

“…It has been suggested that deregulation of cyclin E may be a factor contributing to the malignant phenotype (Keyomarsi and Pardee, 1993;Keyomarsi et al, 1994;Dutta et al, 1995). Recently, Western blotting of 114 breast tumour specimens showed that women with tumours with high cyclin E levels had a significantly increased risk of death and relapse from breast cancer (Nielsen et al, 1996).…”

“…Recently, Western blotting of 114 breast tumour specimens showed that women with tumours with high cyclin E levels had a significantly increased risk of death and relapse from breast cancer (Nielsen et al, 1996). Keyomarsi et al (1994) also showed that the alterations in cyclin E expression became greater with increasing grade and stage (Keyomarsi et al, 1994). However, no studies have examined similar numbers of invasive carcinomas using immunohistochemistry and correlated the findings to clinicopathological parameters.…”

“…In the search for newer markers which can provide information about breast cancer behaviour, attention has recently focused on the role of cyclin E. Previous studies have demonstrated that Received 22 January 1997Revised 29April 1997 Accepted 12 May 1997 Correspondence to: RA Walker overexpression correlates with tumour aggressiveness (Keyomarsi et al, 1994;Nielsen et al, 1996). These studies investigated expression using Western blotting.…”