int‐2 Amplification in breast cancer: Association with decreased survival and relationship to amplification of c‐erbb‐2 and c‐myc

Abstract

Amplification of the int-2 oncogene was measured in a series of breast tumours and related to amplification of the c-myc and c-erbB-2 oncogenes, histopathological features and relapse-free and overall survival. int-2 was amplified in 11%, c-myc in 20% and c-erbB-2 in 27% of the tumours assessed. int-2 amplification was associated with large tumour size (p < 0.05) and reduced relapse-free (p < 0.05) and overall (p < 0.0005) survival. c-myc amplification was associated with poor tumour differentiation (p < 0.05) but had no association with prognosis. c-erbB-2 amplification was associated with low levels of expression of oestrogen receptor mRNA (p < 0.05), poor tumour differentiation (p < 0.05) and shortened relapse-free (p < 0.0001) and overall survival (p < 0.0001). This is the first report of an association between amplification of the int-2 oncogene in breast tumours and a significantly increased risk of death from breast cancer, and suggests that int-2 may be useful for identifying breast-cancer patients having a poor prognosis.

Deregulation of cyclin E and D1 in breast cancer is associated with inactivation of the retinoblastoma protein

“…Of 345 primary breast carcinomas, 50% showed moderate/strong immunohistochemical staining for cyclin D1 expression which was signi®cantly associated with oestrogen receptor positivity and an improved overall survival during observation for up to 20 years (Gillett et al, 1996). Our ®ndings are in agreement with these results, and should be compared to previous investigations demonstrating a negative in¯uence of cyclin D1 gene ampli®cation on disease outcome (Borg et al, 1991;Schuuring et al, 1992b;Henry et al, 1993) and that substantial clinical and experimental evidence points to cyclin D1 as an oncogene, both by in vitro transfection experiments (Jiang et al, 1993;Hinds et al, 1994;Lovec et al, 1994b;Zhou et al, 1995), in studies of transgenetic mice overexpressing cyclin D1 (Lovec et al, 1994a;Wang et al, 1994b) and in the ®ndings of a clonal rearrangement of the gene in mantel cell lymphomas (Withers et al, 1991) and parathyreoidea adenomas (Motokura et al, 1991). The prognostic discrepancy between cyclin D1 protein expression and gene ampli®cation analysis could be due to di erences in disease stages of patients in the various studies and the problem of de®ning a truly pathological cyclin D1 overexpression and not induced by mitogenes and steroids in receptor positive tumours .…”

Prognostic value of CCND1 gene status in sporadic breast tumours, as determined by real-time quantitative PCR assays

“…The frequencies of CCND1 amplification (11.2%) and overexpression (33.6%) are in agreement with those previously reported in the literature (Ali et al, 1989;Borg et al, 1991;Schuuring et al, 1992;Henry et al, 1993;McIntosh et al, 1995;Gillett et al, 1996;Barbareschi et al, 1997;Jares et al, 1997;Nielsen et al, 1997;Kenny et al, 1999). Joint analysis of the CCND1 gene at both the mRNA and DNA levels showed that patients with a good outcome had CCND1-unamplified-overexpressed tumours while those with a poor outcome had CCND1-amplified tumours.…”

“…Joint analysis of the CCND1 gene at both the mRNA and DNA levels showed that patients with a good outcome had CCND1-unamplified-overexpressed tumours while those with a poor outcome had CCND1-amplified tumours. Our results confirm the poor outcome associated with CCND1 amplification (Ali et al, 1989;Borg et al, 1991;Schuuring et al, 1992;Henry et al, 1993). More interestingly, they suggest that CCND1 amplification status should be taken into account when studying the prognostic significance of CCND1 overexpression.…”

“…Transgenic mice carrying the CCND1 gene driven by the mouse mammary tumour virus terminal repeat show altered mammary cell proliferation and a high incidence of mammary adenocarcinomas (Wang et al, 1994). Clinical studies have found amplification of 11q13 chromosomal region (which contains CCND1) in 10 -15% of human primary breast cancers (Ali et al, 1989;Borg et al, 1991;Schuuring et al, 1992;Henry et al, 1993). However, overexpression (at both the mRNA and protein levels) is seen in about 50% of cases, suggesting that mechanisms other than DNA amplification may dysregulate cyclin D1 expression (McIntosh et al, 1995;Gillett et al, 1996;Barbareschi et al, 1997;Jares et al, 1997;Nielsen et al, 1997;Kenny et al, 1999).…”

“…However, clinical studies have produced unexpected results. Indeed, CCND1 amplification has been linked to poor outcome (Ali et al, 1989;Borg et al, 1991;Schuuring et al, 1992;Henry et al, 1993), whereas overexpression of cyclin D1, as determined by immunohistochemical methods, has been linked to good outcome (Gillett et al, 1996). The latter association could be explained by a link between cyclin D1 overexpression and well-differentiated, ER-positive carcinomas, which carry a better prognosis.…”