Abstract P3-08-02: Expression of lipid metabolism genes in tumor and contralateral unaffected breast are conversely associated with tumor estrogen receptor status
Authors: Shidfar Ali , Ivancic David , Sullivan Megan E , Patankar Pranjal , Khan Seema A , Wang Jun 
Published: May 2015

Background: The identification of women at risk for ER- cancer would allow optimization of breast cancer prevention strategies by guiding their recruitment to studies of agents with efficacy against ER- cancer and sparing them the toxicity of prevention agents effective only against ER+ cancer. In our previous studies, we identified lipid metabolism (LiMe) gene set in rFNA samples from contralateral unaffected breast (CUB) that was associated with tumor ER status. In the current study, we further validate LiMe gene expression in tumor and CUB at the mRNA and protein levels.

Methods: Tissue samples from 56 bilateral mastectomy cases (28 ER+ and 28 ER-) and 28 healthy reduction mammoplasty (RM) controls were used. The ER+ cases, ER- cases and controls were matched by age, race and menopausal status. We performed laser capture microdissection of epithelial cells in fresh frozen tissues from tumor and unaffected breast. Total RNA was extracted and LiMe genes were detected using Taqman low density gene expression arrays. The difference among groups was analyzed using ANOVA with Sidak multiple comparison adjustment. Three proteins (HMGCS2, ACSL3 and HPGD) were detected in FFPE sections of tumor and CUB tissues using immunohistochemistry.

Results: Among the 13 LiMe genes, 6 genes (DHRS2, HMGCS2, UGT2B7, UGT2B11, UGT2B28 and GLYATL1) were significantly higher in CUB of ER- cases compared to CUB of ER+ cases (2.2-2.9 fold, P&lt;0.05). In contrast, the expression of 5 genes (DHRS2, HMGCS2, UGT2B11, UGT2B28 and GSTT2) was significantly lower in ER- tumor compared to ER+ tumor (0.11-0.37 fold, P&lt;0.05). Immunohistochemistry of HMGCS2, ACSL3 and HPGD confirmed this pattern: protein levels were higher in ER- CUB than ER+ CUB, but lower in ER- tumor than in ER+ tumor. When CUB samples were compared with healthy controls, 7 genes (DHRS2, HMGCS2, UGT2B11, UGT2B28, GLYATL1, ALOX15B and SERHL) showed significantly higher expression in CUB of ER- cases (2.5-9.6 fold, P&lt;0.05), but not in CUB of ER+ cases. Four genes (ACSL3, APOD, AKR1B15 and HPGD) did not show any significant difference among groups.

Conclusion: Differential expression of the LiMe genes in the CUB is associated with ER- index tumors and may characterize the environment leading to the development of ER- breast cancer. The converse patterns in tumor and CUB by ER status suggest that LiMe genes may be regulated by different mechanisms in benign and malignant tissues. These genes are potential risk biomarkers of ER- breast cancer and generate novel etiologic hypotheses regarding the development of ER- versus ER+ disease.

GeneER-C vs ER+CER-T vs ER+TER-C vs RMER+C vs RMDHRS22.4 (0.034)*0.16 (0.042)*6.0 (0.014)*1.3HMGCS22.9 (0.050)*0.15 (0.0095)*6.5 (0.006)*2.2UGT2B72.2 (0.004)*0.771.81.0UGT2B112.4 (0.019)*0.11 (0.0068)*9.6 (0.013)*2.0UGT2B282.3 (0.009)*0.15 (0.018)*2.8 (0.029)*1.5GLYATL12.9 (0.010)*0.374.3 (0.026)*1.4GSTT21.10.37 (0.040)*1.51.3ALOX15B1.60.562.5 (0.016)*1.5SERHL1.80.294.9 (0.0047)*1.4ER-C: ER- CUB; ER+C: ER+ CUB; ER-T: ER- tumor; ER+T: ER+ tumor; RM: reduction mammoplasty

Citation Format: Ali Shidfar, David Ivancic, Megan E Sullivan, Pranjal Patankar, Seema A Khan, Jun Wang. Expression of lipid metabolism genes in tumor and contralateral unaffected breast are conversely associated with tumor estrogen receptor status [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 P3-08-02.