The interferon regulatory factor-1 (
IRF1) gene mediates interferon and other cytokine effects and exhibits antitumor activity in vivo and in vitro.
IRF1 can also reverse the oncogenic transformation of cells induced by the overexpression of both
RAS and
MYC in mouse models [
1]. Since functional roles for
RAS and
MYC are established in human breast cancer [
2,
3], a loss of
IRF1 function might be important in this disease. Functionally, overexpression of
IRF1 reduces [
4,
5], and a dominant negative
IRF1 construct increases [
4], tumorigenesis of human breast cancer xenografts. We and others have identified
IRF1 as a key regulator of breast cancer cell survival [
5–
8] that can activate a caspase cascade [
4] and induce apoptosis [
5,
6]. More specifically, the proapoptotic effects of
IRF1 include activation/regulation of caspases-1 [
9], −3 [
4], −7 [
4,
10], and −8 [
4,
11].
IRF1 can also induce apoptosis through both
TP53-dependent and
TP53-independent signaling [
9,
12].
TP53 is often mutated in breast cancer [
13], and many breast tumors initially respond to drugs and hormones through
TP53-dependent and
TP53-independent signaling. We have shown that
IRF1 is a key determinant of responsiveness to antiestrogen therapies in breast cancer [
6,
7].
Whether
IRF1 is a true tumor suppressor gene (TSG) in breast cancer is unknown. Established TSGs often show evidence of homozygous or heterozygous gene loss. For instance, while loss of
BRCA1 function in inherited breast cancers is usually a consequence of gene mutation(s), loss of
BRCA1 expression in sporadic breast cancers is often the result of loss of heterozygosity (LOH) accompanied by hypermethylation of a CpG island in the 5′ region close to the transcription start site of the remaining allele [
14,
15].
IRF1 has been implicated as a putative TSG in leukemias and preleukemic myelodysplasias, and
IRF1 is either mutated or rearranged in some hematopoietic disorders [
16].
IRF1 was shown to be the true target of frequent deletions (LOH) in esophageal cancer [
17] and gastric cancer [
18].
IRF1 is located at 5q31.1, a region shown to be commonly lost in two large studies evaluating breast tumors by chromosomal comparative genomic hybridization (CGH). Deletion of 5q12-31 is detected in 11% of sporadic breast cancers [
19] and 5q deletion is seen in 86% of
BRCA1 tumors [
20]. More recently, a high-resolution array-CGH study has shown loss at 5q31.1 in 50% of
BRCA1-positive breast cancers [
21]. Whether loss at the
IRF1 locus is the driver in these cancers and whether
IRF1 gene loss occurs in sporadic breast cancers are unknown.
IRF1 is inactivated by a point mutation in gastric cancer, suggesting that the loss of function of
IRF1 may be critical for the development of this disease [
18]. When attempting to generate an
IRF1 riboprobe from MCF-7 breast cancer cells mRNA, we found a single nucleotide polymorphism (SNP) in the
IRF1 coding region [
22] and a novel
IRF1 splice variant (K. B. Bouker; unpublished observations). The
IRF1 A4396G SNP is more frequent in human breast cancer cell lines than in the general population and is more frequently expressed in African-American than Caucasian subjects [
22]. It is not known whether
IRF1 A4396G contributes to the earlier age [
23] or higher stage at diagnosis [
24] or the lower overall survival rate of African-American compared with non-Hispanic white and Hispanic women [
25]. When considered together, these observations strongly suggest that
IRF1 may be a TSG in breast cancer. Since one of the key features of TSGs is somatic loss, we designed this study to determine the incidence of
IRF1 loss in a series of 52 invasive breast tumors. Considering that
IRF1 LOH might be expected to reduce mRNA expression, we also explored whether low
IRF1 mRNA expression is associated with poor clinical outcomes in breast cancer patients.
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