Downregulation of the potential suppressor gene IGFBP-rP1 in human breast cancer is associated with inactivation of the retinoblastoma protein, cyclin E overexpression and increased proliferation in estrogen receptor negative tumors

Abstract

The complex insulin-like growth factor network of ligands, receptors and binding proteins has been shown to be disturbed in breast cancer. In addition to defects in proteins controling cell cycle checkpoints, this type of aberrations could a ect tumor growth and survival thereby in¯uencing both tumor aggressiveness and potential response to treatments. We have previously identi®ed the T1A12/mac25 protein, which is identical to the IGFBP-rP1, as a di erentially expressed gene product in breast cancer cells compared with normal cells. Here we compare the expression of IGFBP-rP1 in 106 tumor samples with known status of cell cycle aberrations and other clinicopathological data. This was done using a tumor tissue section array system that allows for simultaneous immunohistochemical staining of all samples in parallel. Cytoplasmic staining of variable intensity was observed in most tumors, 15% lacked IGFBP-rP1 staining completely, 20% had weak staining, 32% intermediate and 33% showed strong staining. Low IGFBP-rP1 was associated with high cyclin E protein content, retinoblastoma protein (pRb) inactivation, low bcl-2 protein, poorly di erentiated tumors and higher stage. There was a signi®cantly impaired prognosis for patients with low IGFBP-rP1 protein tumors. Interestingly, IGFBP-rP1 showed an inverse association with proliferation (Ki-67%) in estrogen receptor negative tumors as well as in cyclin E high tumors suggesting a separate cell cycle regulatory function for IGFBP-rP1 independent of interaction with the estrogen receptor or the pRb pathway. Oncogene (2001) 20, 3497 ± 3505.

The RING-H2 protein RNF11 is overexpressed in breast cancer and is a target of Smurf2 E3 ligase

“…TMA technology allowed for a rapid and simultaneous analysis of RNF11 protein expression in 125 primary tumours microarrayed in duplicate by immunohistochemical staining using anti-RNF11 antibody (Kononen et al, 1998;Landberg et al, 2001). Comparison of RNF11 expression between breast, prostate, head and neck, kidney, colon and lung cancers revealed that the majority of our tumour array specimens produced clear immunostaining without any detectable background, and the morphology of the tissues was well preserved (Figure 1).…”

“…Comparison of RNF11 expression between breast, prostate, head and neck, kidney, colon and lung cancers revealed that the majority of our tumour array specimens produced clear immunostaining without any detectable background, and the morphology of the tissues was well preserved (Figure 1). To facilitate comparison of our results with published data, we employed the commonly used semiquantitative evaluation of protein expression based on distinct differences between strong, moderate and lack of staining in tumour specimens developed with immunoperoxidase methods (Kononen et al, 1998;Landberg et al, 2001). RNF11 was markedly overexpressed in breast and to a somewhat lesser extent in pancreatic as well as colon cancer samples, whereas it was only weakly expressed in prostate and renal cell carcinomas (Table 1, Figure 1).…”

“…The primary RNF11 antibody (0.4 mg ml À1 , 1 : 125 dilution) was used to probe TMA sections processed and evaluated as reported previously (Landberg et al, 2001). For negative controls, RNF11 antibody was preincubated with the RNF11 peptide (10 : 1 ratio with antibody) used for immunisation 1 h prior to the reaction with the TMA.…”

siRNA-mediated AML1/MTG8 depletion affects differentiation and proliferation-associated gene expression in t(8;21)-positive cell lines and primary AML blasts

“…For instance, IGFBP7 (IGFBP-rP1, MAC25) binds to insulin and insulinlike growth factor 1, thereby inhibiting proliferation (Oh et al, 1996;Yamanaka et al, 1997). Interestingly, IGFBP7 expression is downregulated in several types of cancer, and restoration of its expression induces cellular senescence or apoptosis (Swisshelm et al, 1995;Lopez-Bermejo et al, 2000;Landberg et al, 2001;Mutaguchi et al, 2003). The transmembrane protein MS4A3 (HTm4) inhibits G1-S cell cycle transition in haematopoietic cells by binding to cyclin-dependent kinase (CDK)-associated phosphatase-CDK2 complexes (Donato et al, 2002).…”

Insulin-like growth factor-binding protein 7 alters the sensitivity to interferon-based anticancer therapy in hepatocellular carcinoma cells

“…The microarray analysis identified that insulin-like growth factor (IGF)-binding protein 7 (IGFBP7), which has been reported to have a tumour-suppressive activity through the induction of apoptosis in some cancers, was a key gene related to the response to this therapy (Burger et al, 1998;Landberg et al, 2001;Mutaguchi et al, 2003;Sato et al, 2007;Lin et al, 2008;Wajapeyee et al, 2008). Furthermore, we confirmed that IGFBP7 significantly correlated with the response to IFN-a/5-FU therapy in genetic manipulation experiments and to the clinical response in HCC tissue samples.…”