Abstract

Introduction

Materials & Methods

Results

Discussion & Conclusion

References

Discussion
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The expression of ERC4, ERD3 and ERD5 variant mRNAs relative to WT-ER mRNA expression within adjacent normal and neoplastic human breast tissues was investigated using previously described semi-quantitative RT-PCR assays (7, 9). These assays allow the determination of the expression of ER-a variant mRNA relative to WT-ER mRNA using a very small amount of starting material, and offer the advantage of allowing investigators to work with histopathologically well characterized human breast tissue regions.

A trend towards a higher ERC4 mRNA relative expression in tumor components compared to the normal adjacent tissue component has been observed in the cohort studied (12 out of 18 cases). This difference reached statistical significance when considering the ER positive/PR positive subgroup (n=9, p= 0.019). This result is in agreement with our previous data obtained by comparing ERC4 mRNA expression between independent normal reduction mammoplasty samples and a group of ER positive/PR positive breast tumors (9). ERC4 variant mRNA has been previously shown to be more highly expressed in ER positive tumors showing poor prognostic characteristics (presence of more than 4 axillary lymph nodes, tumor size >2 cm, aneuploid, high % S-phase cells) than in ER positive tumor with good prognostic characteristics (absence of axillary lymph node, tumor size < 2 cm, diploid, low % S-phase cells) (11). Moreover, in this previous study, an higher ERC4 mRNA expression has also been observed in ER positive/PR negative tumors, as compared to ER positive/PR positive tumors (11). Interestingly we also have recently reported similar levels of expression of ERC4 mRNA in primary breast tumors and their concurrent axillary lymph node metastases (12). Taken together, these data suggest that the putative role of the ERC4 variant protein might be important in the earliest phases of breast tumorigenesis rather than in the later stages of breast cancer progression.

A trend towards a higher relative expression of ERD3 mRNA in the normal breast tissue components compared to adjacent neoplastic tissue was found (10 out of 13 cases), which reached statistical significance when the ER positive subgroup was only considered. These data are in agreement with the recently published report of Erenburg et al. who showed a decreased relative expression of ERD3 mRNA in neoplastic breast tissues and breast cancer compared with independent reduction mammoplasty and breast tumor (10). Transfection experiments performed by these investigators showed that the activation of the transcription of the pS2 gene by estrogen was drastically reduced in the presence of increased ERD3 expression. Moreover, ERD3 transfected MCF-7 cells had a reduced saturation density, exponential growth rate and in vivo invasiveness, as compared to control cells. These data led the authors to hypothesize that the reduction of ERD3 expression could be a pre-requisite for breast carcinogenesis to proceed.

We observed a significantly higher relative expression of ERD5 mRNA in breast tumor components compared to matched adjacent normal breast tissue. These data confirm our previous observations performed on non-matched normal and neoplastic human breast tissues. Upregulated expression of this variant has already been reported in ER negative/PR positive tumors, as compared to ER positive/PR positive tumor (5), suggesting a possible correlation between ERD5 mRNA expression and breast tumor progression. The exact biological significance of ERD5 variant expression during breast tumorigenesis and breast cancer progression remains unclear.

In conclusion, we have shown that the relative expression of ERC4 and ERD5 variant mRNAs was increased in human breast tumor tissue, as compared to normal adjacent tissue, whereas the expression of ERD3 variant mRNA was decreased in breast tumor tissues. These results, which confirm previous data obtained on independent human breast tissue samples, suggest that the deregulation of the expression of several ER-a variant mRNAs occurs during human breast tumorigenesis. Whether or not a functional role of altered ER-a variant expression is involved in the mechanisms underlying breast tumorigenesis remains to be determined.

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