Cancer Therapy Vol 1, page 103 Cancer Therapy Vol 1, 103-107, 2003.
Expression of RB1CC1, a novel tumor suppressor gene, is inversely correlated with the Ki-67 proliferation index in primary breast cancers Research Article
Koji Teramoto1, Tokuhiro Chano2,3, Yoshitomo Ozaki1, Satoru Sawai1, Noriaki Tezuka1, Keiichi Kontani1*, Shozo Fujino1, Hidetoshi Okabe2 Departments of 1Surgery and 2Clinical Laboratory Medicine, Shiga University of Medical Science, Seta-tsukinowa, Otsu, Shiga 520-2192, Japan, 3PRESTO, Japan Science and Technology Corporation (JST)
__________________________________________________________________________________ *Correspondence: Keiichi Kontani, Department of Surgery, Shiga University of Medical Science, Seta-tsukinowa, Otsu, Shiga 5202192, Japan. Tel.: +81-77-548-2244; Fax: +81-77-544-2901; e-mail address: konbat@belle.shiga-med.ac.jp Key words: RB1CC1, RB1, Ki-67, tumor suppressor gene, breast cancer Received: 14 May 2003; Accepted: 21 May 2003; electronically published: May 2003
Summary Retinoblastoma 1 (RB1)-inducible coiled-coil 1 (RB1CC1) is a key regulator of RB1, and is frequently mutated in breast cancer. We examined RB1CC1 expression using immunohistochemical means and compared it with RB1 and Ki-67 labeling indices as well as estrogen receptor (ER) status in 54 primary breast cancers. RB1CC1 protein expression was absent in 8 cancers (15%), and RB1 protein was significantly decreased or absent in all of the cases lacking RB1CC1. These 8 cases showed no loss of heterozygosity (LOH) at the RB1 locus. Importantly, a loss of RB1CC1 was significantly correlated with a high Ki-67 index (p < 0.0001) and low ER status (p = 0.0123). RB1CC1 expression predicts tumor progression, and its prognostic value should to be established. (Chano, 2002a). We frequently observed RB1CC1 mutations in breast cancer, suggesting that the functional loss of RB1CC1 results in insufficient RB1 expression, which promotes dysregulation of the RB1CC1-RB1 pathway and subsequent tumorigenesis (Chano, 2002c). To clarify the incidence of RB1CC1 anomalies in primary breast cancers, we analyzed RB1CC1 expression by immunohistochemical methods and examined its relationship with various biopathological parameters in breast cancers from 54 patients. The important findings of the present study suggest that a loss of RB1CC1 expression accelerates cell proliferation.
I. Introduction Inactivation of the retinoblastoma 1 (RB1) gene is considered to play a central role in the pathogenesis of many human malignant neoplasms (Kamb, 1995; Taya, 1997; Kaelin et al, 1999). RB1 is also involved in tumorigenesis and tumor progression (Lemoine, 1994; T’Ang, 1998; Kaelin et al, 1999), and its expression is inversely correlated with its proliferative activity in breast cancer (T’Ang and Fung, 1991). The RB1 locus is genetically altered in 3 to 37% of breast cancers (Varley et al, 1989; Thorlacious et al, 1991; Lemoine, 1994; T’Ang, 1998; Kaelin et al, 1999; Bieche and Lidereau, 2000). However, it is not always responsible for the absence of RB1 expression under such conditions (Varley et al, 1989; Bieche and Lidereau, 2000), and other factors are probably involved in this phenomenon. RB1-inducible coiled-coil 1 (RB1CC1) is thought to be a transcription factor because it is in fact localized to the nucleus and it contains a nuclear localization signal, a leucine-zipper motif and a coiled-coil structure (Chano, 2002a,b). RB1CC1 is co-expressed with RB1 in various cancers and normal tissues (Chano, 2002a,b), where it functions as an inducible regulator of RB1 expression
II. Materials and methods A. Specimens We analyzed formalin-fixed and paraffin-embedded primary breast cancer tissues resected from 54 patients at the Shiga University of Medical Science Hospital between July 1996 and December 2001. The Ethics Committee of our institution approved the use of these specimens, which were histologically classified according to the World Health Organization (WHO) guidelines.
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