Breast cancer is the second leading cause of cancer death for women in the United States. In 2005, about 215,000 cases of invasive breast cancer (IBC) and 50,000 cases of ductal carcinoma in situ will be diagnosed and 40,000 women will die of IBC in the US. Yet there is presently no molecular marker that can be used to detect a precancerous state or identify which premalignant lesions will develop into invasive breast cancer. Here we report the gene expression analysis of atypical ductal hyperplastic tissues from patients with and without a history of breast cancer. We identify MMP-1 as a candidate marker that may be useful for identification of breast lesions that can develop into cancer.
Four different human tissues and breast cancer cell lines were screened to identify exon deletion variant transcripts of estrogen receptor L L (ERL L) by reverse transcription-polymerase chain reaction using the 'splice targeted primer approach' that amplifies each category of exon deleted variants as a separate gene population. A total of 10 different variant mRNAs that have deletions in various combination of exons were identified by sequence analysis. They were exon 2v v; exons 2 and 5^6v v; exon 3v v; exon 4v v; exon 5v v; exons 5 and 2v v; exon 6v v; exons 6 and 2v v; exons 6, 2^3v v; and exons 5^6v v. In some cases, deletion of an exon appears to be associated with a mutation of a specific base. Although ERK K and ERL L are highly homologous, have identical exon and functional domain organization, exhibit similar ligandbinding profiles and interact with identical DNA response elements, the sequence of exon skipping in ERL L pre-mRNA appears to be distinct from that of ERK K mRNA. Furthermore, results described here also suggest that alternate splicing of ERL L mRNA is tissue specific. The presence of a ERL L variant profile together with other ER isoforms in a tissue may have functional implications in binding and response to a particular ligand. ß
We describe here the cloning and functional characterization of two unique ER isoforms, ERbeta4 and ERbeta5. The full length ERbeta4 and ERbeta5 were identified by asymmetric PCR using human ovary cDNA, cloning, and sequence analyses. Both receptors share identical sequences with ERbeta1 from exon 1 to exon 7. In the place of exon 8, ERbeta4 has unique sequences arising from a region downstream of the ERbeta gene and upstream of the SYNE2 gene. ERbeta5 has sequences arising from retention of the 5' end of the intron between exon 7 and 8. Both receptors bind promoter sequences on DNA but do not bind estrogen. They translocate to the nucleus and exhibit three to four times higher estrogen-independent transcriptional activity than ERbeta1. When co-transfected with ERalpha, they predominantly form heterodimers and negatively regulate its transcriptional activity. Estrogen-independent transcriptional activity of ERbeta5, but not ERbeta4, was inhibited by ERalpha, demonstrating for the first time that ERalpha regulates ERbeta. Tissue-specific expression of ERbeta4 and ERbeta5, together with their ligand-independent transcriptional properties and ERalpha modulating activities, could have a number of implications in seemingly unlinked biological processes regulated by estrogen.
We have investigated the expression of two estrogen receptor h (ERh) isoforms, ERh1and ERh5, which activate gene transcription independent of estrogen or growth factors, in ERa-negative breast cancer tissues.We report here, for the first time, that ERa-negative tissues express significant levels of ERh1 and ERh5, and their expression levels are not different from levels in ERapositive tumors. However, significant differences exist between the two racial groups, African American and Caucasian, in that the patients from the former group express higher levels of ERh1and ERh5 but not ERa. These two transcription factors could be potential molecular targets for designing chemopreventive drugs to treat ERa-negative breast cancers.
DCIS = ductal carcinoma in situ; ER = estrogen receptor; HB = homeobox; HD = homeodomain; PR = progesterone receptor; RT-PCR = reverse transcription polymerase chain reaction. (Print ISSN 1465-5411; Online ISSN 1465-542X). This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
Breast Cancer Research Vol 5 No 4 Fu et al.
Research article
Correlation of expression of BP1, a homeobox gene, with estrogen receptor status in breast cancer
AbstractBackground: BP1 is a novel homeobox gene cloned in our laboratory. Our previous studies in leukemia demonstrated that BP1 has oncogenic properties, including as a modulator of cell survival. Here BP1 expression was examined in breast cancer, and the relationship between BP1 expression and clinicopathological data was determined.
Methods:Total RNA was isolated from cell lines, tumors, and matched normal adjacent tissue or tissue from autopsy. Reverse transcription polymerase chain reaction was performed to evaluate BP1 expression. Statistical analysis was accomplished with SAS.Results: Analysis of 46 invasive ductal breast tumors demonstrated BP1 expression in 80% of them, compared with a lack of expression in six normal breast tissues and low-level expression in one normal breast tissue. Remarkably, 100% of tumors that were negative for the estrogen receptor (ER) were BP1-positive, whereas 73% of ER-positive tumors expressed BP1 (P = 0.03). BP1 expression was also associated with race: 89% of the tumors of African American women were BP1-positive, whereas 57% of those from Caucasian women expressed BP1 (P = 0.04). However, there was no significant difference in BP1 expression between grades I, II, and III tumors. Interestingly, BP1 mRNA expression was correlated with the ability of malignant cell lines to cause breast cancer in mice.
Conclusion:Because BP1 is expressed abnormally in breast tumors, it could provide a useful target for therapy, particularly in patients with ER-negative tumors. The frequent expression of BP1 in all tumor grades suggests that activation of BP1 is an early event.
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