Arylamine N‐acetyltransferase 1 expression in breast cancer cell lines: A potential marker in estrogen receptor‐positive tumors

Abstract

The prognosis for patients with estrogen receptor (ER)-positive breast cancer has improved significantly with the prescription of selective ER modulators (SERMs) for ER-positive breast cancer treatment. However, only a proportion of ER-positive tumors respond to SERMs, and resistance to hormonal therapies is still a major problem. Detailed analysis of published microarray studies revealed a positive correlation between overexpression of the drug metabolizing enzyme arylamine N-acetyltransferase type 1 (NAT1) and ER positivity, and increasing evidence supports a biological role for NAT1 in breast cancer progression. We have tested a range of ER-positive and ER-negative breast cancer cell lines for NAT1 enzyme activity, and monitored promoter and polyadenylation site usage. Amongst ER-positive lines, NAT1 activities ranged from 202 +/- 28 nmol/min/mg cellular protein (ZR-75-1) to 1.8 +/- 0.4 nmol/min/mg cellular protein (MCF-7). The highest levels of NAT1 activity could not be attributed to increased NAT1 gene copy number; however, we did detect differences in NAT1 promoter and polyadenylation site usage amongst the breast tumor-derived lines. Thus, whilst all cell lines tested accumulated transcripts derived from the proximal promoter, the line expressing NAT1 most highly additionally initiated transcripts initiating at a more distal, "tissue"-specific promoter. These data pave the way for investigating NAT1 transcripts as candidate prognostic markers in ER-positive breast cancer.

miR-1290 and its potential targets are associated with characteristics of estrogen receptor α-positive breast cancer

“…Several studies have shown higher mRNA and protein expression of NAT1 in ER-positive breast cancer compared with the expression in ER-negative disease (Perou et al 2000, Adam et al 2003, Tozlu et al 2006, Wakefield et al 2008. Moreover, it was reported that high expression of NAT1 was correlated with better outcome in ER-positive breast cancer (Bieche et al 2004, Dolled-Filhart et al 2006.…”

Characterization of N-Acetyltransferase 1 Activity in Human Keratinocytes and Modulation by para-Phenylenediamine

“…In addition, several nonsubstrates such as tamoxifen (Lee et al, 1997) and cisplatin (Ragunathan et al, 2008) are known to down-regulate its activity. It is noteworthy that the latter are commonly used as antitumor agents, and recent data suggest that cisplatin-induced NAT1 inactivation contributes to their beneficial effects, not least because of increasing evidence for a dysregulation of NAT1 in certain cancer cells (Adam et al, 2003;Wakefield et al, 2008).…”

Glucocorticoid Receptor-Mediated Transcriptional Regulation of N-acetyltransferase 1 Gene Through Distal Promoter

“…Also, if our findings can be applied to tissues other than the liver-e.g., breast or prostate, where (HUMAN)NAT1 has been shown to highly contribute to tumor malignancy-concerns should arise about the administration of glucocorticoids to cancer patients. In this context, it should be noted that Wakefield et al (6) showed that among different ER + breast cancer cell lines, only those with the highest NAT1 activity (ZR-75-1) had NAT1 transcripts originating from P3, suggesting the inducibility/activation of this promoter and potential pertinence of our findings to tissues are different from the liver. The recurrent prescription of glucocorticoids as cancer co-treatment (42) could thus exacerbate cancer malignancy, due to the increasing evidence of (HUMAN)NAT1 overexpression and its contribution to tumor initiation and progression.…”

“…It was also shown that the (HUMAN)NAT1 gene was down-regulated in late-stage breast cancer (6). In addition, DNA hypomethylation in the (HU-MAN)NAT1 gene was reported in cancerous breast tissues (7).…”

“…(HUMAN)NAT1 over-expression has been shown in human breast carcinomas (4)(5)(6) and is linked to enhanced growth and resistance to the cytotoxic drug etoposide in normal breast luminal epithelial cells (4). It was also shown that the (HUMAN)NAT1 gene was down-regulated in late-stage breast cancer (6).…”