This study does not provide evidence for mutation in the coding exons of the P450arom gene which would account for either the absence of aromatase activity or its changed sensitivity to 4-OHA in breast cancers.
Our results underscore the importance of aromatase inhibitors as effective agents in treatment of hormone-responsive breast cancer, since aromatase inhibitors reduce local aromatase activity as well as blood estradiol levels.
Studies designed to investigate whether increased local aromatase activity in breast adipose tissue influences the growth of breast cancers have yielded discrepant results.
The object of the present study was to determine the distribution of these various exon-specific transcripts in breast adipose tissues from cancer-free women undergoing reduction mammoplasty and from patients with breast cancer, because this would provide important clues as to the nature of the factors regulating aromatase expression in these sites.
The aromatase mRNA levels in these breast cancer tissues (4.53 +/- 0.66 x 10(-3) attomoles/micrograms RNA) were significantly (P < 0.01) higher than those in 16 nonmalignant breast tissues (1.73 +/- 0.40 x 10(-3) amol/micrograms RNA).
The analysis has revealed that exons I.3 and PII are the two major exon Is present in aromatase mRNA isolated from breast tumors, suggesting that promoters I.3 and II are the major promoters driving aromatase expression in breast cancer and surrounding adipose stromal cells.
Our own studies have demonstrated overexpression of int5/aromatase in mammary glands of virgin and postlactational females leads to the induction of various preneoplastic and neoplastic changes that are similar to early breast cancer, that may, in turn, increase the risks for developing breast cancer.
The expression levels of aromatase mRNA in breast cancer tissues were significantly higher than those in regions distal to tumours or in non-malignant breast tissues.
The analysis revealed that exons I.3 and PII are the two major exons I present in aromatase mRNA isolated from breast tumors, suggesting that promoters I.3 and II are the major promoters driving aromatase expression in breast cancer and surrounding adipose stromal cells (ASCs).
While the control mechanism of aromatase expression in breast cancer tissue is not yet fully understood, aromatase-inhibitor therapy is considered for second-line treatment in patients who fail anti-estrogen therapy.
However, in half the cases of breast cancers, switching of the alternative exons 1 from exon 1b to ovary-specific exon 1 (exon 1c) was observed, and expression levels of aromatase mRNA in breast cancer tissues were significantly higher than those in the distal regions to tumors or in non-malignant breast tissues.
We now report that ICI 182,780 is also an inhibitor of aromatase activity in fibroblasts isolated from the normal human breast as well as other carcinoma cell lines that express aromatase (MCF-7Ca breast cancer and JEG-3 choriocarcinoma).
Our conclusion is that constitutional genetic variation at the Cyp19 locus is associated with the risk of developing breast cancer, with the 171-bp allele serving as the high-risk allele.
Aromatase expression in breast cancer and the surrounding adipose cells is directed mainly by promoters I.3 and II, while its expression in the normal breast adipose tissue is driven by promoter I.4.