Abstract P4-14-05: Clues to the abundance of triple negative breast cancer in women of African descent
Authors: Sauder Candice AM , Koziel Jillian E , Choi Mi Ran , Feng Gang , Herbert Brittney-Shea , Clare Susan E 
Published: May 2015

Background: Triple negative breast cancer (TNBC) is over-represented in indigenous African women and in women of African descent. The majority of women diagnosed with breast cancer in Nigeria, Uganda and Kenya have TNBC. Dr. Lisa Newman and colleagues reported TNBC rates of 83.3% in Ghana, 41.4% among African-Americans (AA) and 15.4% for Caucasian-Americans (C)(Stark et al, Cancer, 2010). The abundance of TNBCs in both African and African-American women has yet to be explained and the incidence rates suggest that there may be a genetic predisposition to this particularly aggressive form of breast cancer.

Lipocalin 2 (LCN2), also known as NGAL, is a small-secreted glycoprotein. It chelates iron making this element unavailable to infectious agents that require it for growth including salmonella and tuberculosis bacilli, and Plasmodium parasites. Inactivation of the tumor suppressor gene "hypermethylated in cancer 1" (HIC1) results in upregulation of LCN2 at the mRNA and protein levels. Recently, it was shown that HIC1 is silenced in TNBC when but not in the luminal and HER2 subtypes (Cheng et al, Cancer Research, 2013). The purpose of this study was to determine if the expression of either of these two genes, LCN2 and HIC1, differs in breast epithelia as a function of race.

Methods: Multiple epithelial cell lines from normal, healthy breast tissue donated to the Susan G. Komen for the Cure Tissue Bank at the IU Simon Cancer Center were established (Sauder et al, BMC Cell Biology, 2014). Six epithelial cell lines from AA and six from C donors were matched for age, menstrual status and Gail risk score. RNA and DNA were extracted from the cultured cells. Genome-wide gene expression was assayed using the IlluminaHumanWG-6 v3 Expression Bead Chip. Differential gene expression was determined using PADE (PAirwise Differential Expression; Expression Analysis, Inc). SNPs were identified using the Illumina Human 1M-Duo BeadChip.

Results: The expression of LCN2 in the normal breast epithelia of AA donors was 20-fold that in C donors (p=0.01). The expression of HIC1 was 1.94-fold less in AA but this did not reach statistical significance (p=0.29). Analysis of HIC1 DNA data was complicated by the small number of samples and the paucity of probes within HIC1 on the Human 1M-Duo BeadChip. The search, therefore, was extended 10,000 bases upstream. There appears to be a heterozygous deletion in two of the AA and one of the C donors in this region of the genome. We then searched the ENSEMBLE database to determine if there are any SNPs in HIC1 or its promoter region which differ by Race; only rs8065350 did so. This SNP is in the promoter region of this gene and occurs within the ENCODE Chip-Seq. tracks of REST/NRSF and Elf1.

Conclusions: LCN2 expression may provide a survival advantage to individuals residing in regions of the world where iron-requiring infectious agents are endemic. Iron and folic acid supplementation in a clinical trial in East Africa resulted in significantly more deaths and hospitalizations from infectious diseases. LCN2 expression may provide innate immunity while at the same time predisposing women to TNBC in an as of yet undetermined manner. It is interesting to note that LCN2 expression is increased in prostate carcinoma in AA men when compared to C.

Citation Format: Candice AM Sauder, Jillian E Koziel, Mi Ran Choi, Gang Feng, Brittney-Shea Herbert, Susan E Clare. Clues to the abundance of triple negative breast cancer in women of African descent [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-14-05.