Fine-needle aspirant samples taken from the healthy contralateral breast of patients undergoing surgery for breast cancer contained newly identified genetic markers that were expressed differently in estrogen receptor–negative and estrogen receptor–positive tumors.
The findings suggest that a metabolic derangement in lipid processing may precede the development of a breast tumor.
All of these genes are involved in lipid metabolism, an unexpected finding that speaks to the long-observed relationship between weight and breast cancer risk, Dr. Seema Khan and her colleagues wrote in the March issue of Cancer Prevention Research (2013 [doi:10.1158/1940-6207.CAPR-12-0304]).
Dr. Seema Khan
"This was interesting because obesity is a breast cancer risk factor for postmenopausal women, but obese women are generally thought to be at increased risk for hormone-sensitive cancer," Khan said in a press statement. "We were surprised to see that some of these genes that are associated with lipid metabolism, or the metabolism of fats, are actually more highly expressed in the unaffected breasts of women with estrogen receptor–negative breast cancer."
The investigators, all from Northwestern University in Chicago, conducted their initial analysis on a set of 30 breast cancer patients – 15 with ER-negative tumors and 15 with ER-positive tumors. They then validated their results on 36-subjects, 12 with ER-negative cancers, 12 with ER-positive cancers, and 12 controls. All of the women in the study were matched for age, menopausal status, weight, and, in the patients, HER2 status. All subjects were followed for a minimum of 3 years.
Based on RNA extracted from fine-needle aspirations of the subjects’ contralateral breasts, eight unique genes were identified. There was significant differential expression of the genes between the groups. All of the genes were directly involved in lipid metabolism, and seven of them were significantly more common in ER-negative tumors.
Similar results were observed in the validation group, with all eight genes observed to be significantly more common in the ER-negative group than in the ER-positive group.
When the ER-negative cases were compared with the controls, four genes were significantly overexpressed and were observed to be up to six times more common in cases. The genetic markers were similarly expressed in ER-positive cases and in controls, however.
Two of the remaining four genes were significantly underexpressed in ER-positive cases, compared with controls (three and six times less likely to occur, respectively), indicating that both genes may protect against the development of ER-negative tumors. Of the remaining two genes, one was significantly under-expressed in both ER-negative and ER-positive groups, compared with controls (15 and 11 times less common, respectively). This, the authors said, indicates that the gene may protect against both types of cancer.
There were no significant associations between the final gene and either cancer subtype.
A clustering analysis of the eight genes separated the cases into low- mid- and high-expression groups, and also successfully separated the controls from the cases. In this analysis, 70% of the cases in the low-expression group were ER-positive; 67% of the cases in the mid-expression group were ER-positive; and 88% of the cases in the high-expression group were ER-negative.
The analysis also identified a high- and a low-expression group among the 12 controls. Four of these control cases had high-expression profiles, similar to those of the high-expression cases. The cytology of these four samples was atypical in two, borderline in one, and benign in one. The other eight samples had low gene expression and all had benign cytology.
"The potential involvement of lipid metabolism–related genes to ER-negative breast cancer is unexpected, though evidence pointing to a link of lipid/steroid metabolism with ER-negative breast cancer risk and outcomes exists," the authors said. "ER-negative/PR (progesterone receptor)-negative tumors are more common in obese premenopausal women, and large hip circumference has a particularly strong association with premenopausal ER-negative/PR-negative breast cancer. The functions of these genes in relation to lipid modification and elimination, and to transportation and detoxification of distinct lipid compounds, suggest that their expression results in a specific microenvironment of steroid hormone metabolites, which may determine whether initiated cells progress to ER-positive or ER-negative tumors."
None of the authors declared any financial relationships. The study was funded by the Lynn Sage Cancer Research Foundation, the Avon Foundation, and a private contribution.