EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival

Abstract

The EMS1 and CCND1 genes at chromosome 11q13 are ampli®ed in about 15% of primary breast cancers but appear to confer dierent phenotypes in ER positive and ER negative tumours. Since there are no published data on EMS1 expression in large series of breast cancers we examined the relationship of EMS1 expression with EMS1 gene copy number and expression of mRNAs for cyclin D1 and ER. In a subset of 129 patients, where matched tumour RNA and DNA was available, EMS1 mRNA overexpression was associated predominantly with gene ampli®cation (P=0.0061), whereas cyclin D1 mRNA overexpression was not (P=0.3142). In a more extensive series of 351 breast cancers, there was no correlation between cyclin D1 and EMS1 expression in the EMS1 and cyclin D1 overexpressors (P=0.3503). Although an association between EMS1 mRNA expression and ER positivity was evident (P=0.0232), when the samples were divided into quartiles of EMS1 or cyclin D1 mRNA expression, the increase in the proportion of ER positive tumours in the ascending EMS1 mRNA quartiles was not statistically signi®cant (P=0.0951). In marked contrast there was a signi®cant stepwise increase in ER positivity in ascending quartiles of cyclin D1 mRNA (P=0.030). A potential explanation for this dierence was provided by the observation that in ER positive breast cancer cells oestradiol treatment resulted in increased cyclin D1 gene expression but was without eect on EMS1. The relationship between EMS1 expression and clinical outcome was examined in a subset of 234 patients with median follow-up of 74 months. High EMS1 expression was associated with age 450 years (P=0.0001), postmenopausal status (P=0.0008), lymph node negativity (P=0.019) and an apparent trend for worse prognosis in the ER negative subgroup. These data demonstrate that overexpression of EMS1 mRNA is largely due to EMS1 gene ampli®ca-tion, is independent of cyclin D1 and ER expression and, in contrast to cyclin D1, is not regulated by oestrogen. Independent overexpression of these genes may confer dierent phenotypes and disease outcomes in breast cancer as has been inferred from recent studies of EMS1 and CCND1 gene ampli®cation.

Human cortactin as putative cancer antigen

“…Thus, human cortactin appears to display a cancer-restricted immunological pro®le and may be considered as a putative cancer antigen. Moreover, the results of screening of the clone MOBr-140 with a panel of breast cancer and head and neck squamous cell carcinoma sera are in good agreement with published data on average frequency of cortactin gene ampli®cation in primary breast carcinoma and head and neck squamous cell carcinoma (Hui et al, 1998;Meredith et al, 1995).Human immune response to oncogenic proteins has been reported in several studies (Disis and Cheever, 1996) and our ®ndings add human cortactin to this list. Further studies using larger panels of sera and tumor specimens is required to determine whether the presence of antibodies against this gene product in sera of cancer patients correlates with the tumor type and prognosis and could be valuable in cancer diagnostics.…”

“…Thus, human cortactin appears to display a cancer-restricted immunological pro®le and may be considered as a putative cancer antigen. Moreover, the results of screening of the clone MOBr-140 with a panel of breast cancer and head and neck squamous cell carcinoma sera are in good agreement with published data on average frequency of cortactin gene ampli®cation in primary breast carcinoma and head and neck squamous cell carcinoma (Hui et al, 1998;Meredith et al, 1995).…”

“…Cortactin is involved in the signaling pathway of mitogenic receptors and adhesion molecules mediating cytoskeletal reorganization (Schuuring et al, 1993(Schuuring et al, , 1998van Damme et al, 1997;Campbell et al, 1999). Human cortactin maps to the chromosomal band 11q13 which is known to be ampli®ed in about 15% of primary breast carcinomas and 30% of head and neck squamous cell carcinoma (Schuuring, 1995;Meredith et al, 1995;Hui et al, 1998). Such ampli®cation has been also reported for other malignancies, including ovarian and bladder cancer (Bringuier et al, 1996).…”

“…Ampli®cation of cortactin in breast and head and neck carcinomas is associated with poor clinical outcome. (Meredith et al, 1995;Schuuring et al, 1992Schuuring et al, , 1995Hui et al, 1998). Additionally, recent studies have shown the overexpression of cortactin in NIH3T3 cells to result in increased cell invasion/migration in vitro (Patel et al, 1998;Huang et al, 1998).…”

“…The results shown in Figure 2a demonstrate about sixfold overexpression of cortactin transcript in tumor tissue as compared to normal mammary gland tissue. Although overexpression of gene products in cancer can be caused by increased mRNA life span, increased protein stability, or gene ampli®cation (Disis and Cheever, 1996), recent studies indicated that cortactin mRNA overexpression was associated predominantly with gene ampli®cation in some carcinomas (Hui et al, 1998).…”