Is aryl hydrocarbon hydroxylase activity a new prognostic indicator for breast cancer?

Pyykkö, Kaija; Tuimala, Risto; Aalto, L; Perkiö, T

doi:10.1038/bjc.1991.138

Cited by 29 publications

(21 citation statements)

References 19 publications

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“…A role for CYP1A1 and/or factors regulating the expression of this gene in the predisposition, initiation and/or progression of human malignancies has been long recognized, but poorly understood (12,19,48,49). Research efforts that have focused on the positive regulation of CYP1A1expression have failed to identify mechanisms that might contribute to these observed aberrations in gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence also exists that demonstrates a correlation between pulmonary CYP1A1 expression, DNA adduct formation, and smoking in lung cancer patients (14)(15)(16)(17). In pulmonary carcinoma cell lines of various histological origins and in primary human breast cancer, aberrant constitutive expression of CYP1A1 also has been detected (18)(19)(20). These observations suggest that the inappropriate expression of CYP1A1 reflects an alteration in one or more transcriptional control mechanisms that regulate the expression of this gene, and perhaps other genes linked to the etiology of human cancer.…”

Section: Introductionmentioning

confidence: 99%

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Functional characterization of the human CYP1A1 negative regulatory element: modulation of Ah receptor mediated transcriptional activity

Piechocki

Hines

1998

Carcinogenesis

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The mechanisms that underly the regulation of human CYP1A1 have merited considerable attention because of their association both with toxic outcomes and the etiology of several cancers. Previous work conducted in this laboratory has identified a negative regulatory element (NRE) in the 5Ј region of this gene that appeared to modulate CYP1A1 transcriptional activity. This NRE is present in two functional copies, a high affinity 21-bp palindrome centered at position -784, and an additional element found within a GC-rich region between position -728 and -558. In this report, the regulatory function of the NREs in the context of the CYP1A1 promoter was evaluated. This was accomplished by substituting mutated elements for the corresponding wild-type element in a vector that contained human CYP1A1 sequences positions -1140 to ⍣59 directing the transcription of the chloramphenicol acetyltransferase reporter gene. Expression vectors containing specific mutations in each or both NREs were characterized. We show that eliminating the binding of the CYP1A1 repressor protein to one or both repressor motifs results in a significant 2-to 3-fold increase in the inducibility of CYP1A1 promoter activity. Although mutation of both sites appeared to result in an increase in inducibility over that observed with only one site mutated, the effect was not additive. Such aberrant transcriptional activity correlates with the highly inducible aryl hydrocarbon hydroxylase phenotype that is a reported marker for individuals predisposed to lung cancer. Mutation of the NRE, or more likely, the cognate repressor protein(s), may provide a genetic basis for this phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional characterization of the human CYP1A1 negative regulatory element: modulation of Ah receptor mediated transcriptional activity

Piechocki

Hines

1998

Carcinogenesis

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“…Only a limited number of comparable investigations exist that analysed the metabolic capacity of human breast tumour tissue such as the both CYP1A1-mediated ethoxyresorufin O-deethylase (Ìscan et al, 1999) and aryl hydrocarbon hydroxylase activities (Pyykko et al, 1991). Senler et al (1985) found the average cyclohexane (as a substrate for several forms of cytochrome P450) hydroxylase activity in 139 human breast tumour microsome preparations in the range of those observed for untreated rabbit liver microsomes.…”

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confidence: 99%

CYP3A4, CYP2C9 and CYP2B6 expression and ifosfamide turnover in breast cancer tissue microsomes

et al. 2004

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Ifosfamide is a prodrug that requires bioactivation by cytochrome P450 for antitumour activity. Up to now, little is known, to what extent in addition to the liver the ifosfamide metabolism may occur intratumorally. For this purpose, we investigated the expression of CYP3A4, CYP2C9 and CYP2B6 in breast cancer tissue using Western Blotting. Ifosfamide turnover was determined by detection of metabolites of the ifosfamide 4-hydroxylation and N-dechloroethylation in tumour microsomal incubations using HPLC/UV and LC/MS. The results demonstrate that all mammary tumours (n ¼ 11) reveal CYP3A4 expression; contents varied from 0.5 to 63 pmol mg protein À1. CYP2C9 (n ¼ 9) was present in all tested breast tumour samples, too, while CYP2B6 (n ¼ 10) protein could not be detected. All measured breast cancer microsomes (n ¼ 4) showed an ifosfamide N-dechloroethylation capacity in the range from 0.04 to 0.21 pmol min À1 mg protein À1, while metabolites of the 4-hydroxylation could not be determined. In conclusion, the detected presence of CYP3A4 and CYP2C9 in breast tumours offers the possibility of intratumoral turnover of ifosfamide. For the first time in the literature, we could demonstrate a turnover of ifosfamide by microsomal preparations from human breast cancer tissue. A calculated modulation of intratumoral ifosfamide turnover could considerably influence its therapeutic efficiency.

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“…CYPlAl inducibility and polymorphisms may be an important risk factor for lung and colorectal cancers (Kellermann et al, 1973;Kawajiri and Fujiikuriyama, 1991; Sivaraman et al, 1994) and basal CYPlA1-dependent activities in breast tumours are reported to be negative prognostic indicators for disease-free survival of women with breast cancer (Murray et al, 1991;Pyykko et al, 1991);Vickers et al, (1989) (Jaiswal et al, 1985;Ivy et al, 1988;Pasanen et al, 1988;Vickers et al, 1989;Thomsen et al, 1991Thomsen et al, ,1994. Moreover, several cell lines that express the AhR but are ERnegative are not Ah-responsive and these include MDA-MB-231, Hs578T and doxorubicin-resistant MCF-7 breast cancer cells (Jaiswal et al, 1985;Ivy et al, 1988;Pasanen et al, 1988;Harris et al, 1989;Vickers et al, 1989;Thomsen et al, 1991Thomsen et al, ,1994.…”

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confidence: 99%

Effect of transient expression of the oestrogen receptor on constitutive and inducible CYP1A1 in Hs578T human breast cancer cells

Thomsen²,

Porter³

et al. 1996

Br J Cancer

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Summary Hs578T human breast cancer cells are an oestrogen receptor (ER)-negative cell line. Treatment of these cells with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in formation of a 6.9 S nuclear aryl hydrocarbon (Ah) receptor complex, which bound to a [32P]dioxin-responsive element in a gel electrophoretic mobility shift assay. However, TCDD does not induce CYPlAl gene expression or chloramphenicol acetyl transferase (CAT) activity in cells transiently transfected with pRNHllc or pMCAT5.12, which are Ahresponsive plasmids derived from the 5'-flanking region of the human and murine CYP1A1 genes respectively. Restoration of Ah responsiveness was investigated by co-transfecting Hs578T cells with pRNH1 lc or pMCAT5.12 and plasmids that express the ER (hER), Ah receptor (AhR) and AhR nuclear translocator (Arnt) proteins. ER expression resulted in significantly increased basal CAT activity; however, TCDD did not induce CAT activity in the transiently transfected cells. Expression of the AhR or Arnt proteins did not alter basal or inducible CAT activity. Expression of N-or C-terminal truncated ER in Hs578T resulted in differential regulation of Ah responsiveness. In Hs578T cells transiently expressing the ER, which contains Cterminal deletions (amino acids 282-595), basal CAT activity was also increased; however, Ah responsiveness was not restored. In contrast, transient expression of N-terminal-deleted (amino acids 1 -178) ER resulted in a marked decrease in basal CAT activity but a restoration of Ah responsiveness. These results suggest that basal and inducible CAT activity in Hs578T cells transiently transfected with pRNHl lc is modulated differentially by ER domains that are present in the N-and C-terminal regions of the ER.

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Is aryl hydrocarbon hydroxylase activity a new prognostic indicator for breast cancer?

Cited by 29 publications

References 19 publications

Functional characterization of the human CYP1A1 negative regulatory element: modulation of Ah receptor mediated transcriptional activity

Functional characterization of the human CYP1A1 negative regulatory element: modulation of Ah receptor mediated transcriptional activity

CYP3A4, CYP2C9 and CYP2B6 expression and ifosfamide turnover in breast cancer tissue microsomes

Effect of transient expression of the oestrogen receptor on constitutive and inducible CYP1A1 in Hs578T human breast cancer cells

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