Abstract 3541: Characterization of olfactory receptor upregulation in invasive breast cancer
Authors: Masjedi Shirin , Zwiebel Laurence J. , Giorgio Todd D. 
Published: August 2019

Abstract
Despite some progress in early detection and new therapies, breast cancer remains the second most common cause of cancer-related deaths among women. Majority of deaths occur due to invasion and metastasis among triple-negative breast cancer (TNBC) patients. Gene profiling of mammary tumors has enabled identification of novel genes with potential roles in cancer invasion using next generation sequencing technologies. This study is the first to examine upregulation of olfactory receptors (ORs) among a large invasive breast carcinoma population and begins to establish a correlation of OR genes in breast cancer invasion. Invasive breast carcinoma cases from the TCGA database were used. Among data from 1100 unique patients, 960 cases of invasive breast carcinoma had RNAseq of their primary tumors in addition to exome sequencing data. The abundance of all 408 human coding OR genes among the 960 cases were analyzed using a three-factor stratification algorithm, and 30 OR genes were identified as highly abundant among 198 breast invasive carcinoma patients. Supervised clustering of the 198 patients based on the similarity of OR upregulation levels identified five subpopulations among the invasive carcinoma patients in which only one OR gene (OR2A7, OR2B6, OR2C1, OR2W3) was significantly upregulated. Abundance of OR2W3 was significantly elevated in two subpopulations with 30- and 19-fold increase compared to their level of abundance in normal mammary tissue. These two subpopulations were composed of 74% and 70% TNBC tumor subtypes and included all the stage iv cancer patients in the study. Transcript abundance of 21 genes included in the Oncotype DX gene expression diagnostic test was measured for each patient subpopulation. The subpopulation with abundance in OR2W3 was correlated with significant upregulation of invasion genes (CTSV, MMP-11) and the subpopulation with abundance of OR2B6 was correlated with significant upregulation of proliferation genes (MKI67, AURKA, BIRC67, CCNB1, MYBL2). Interestingly, only the cases with significant upregulation of OR2W3 were correlated with significantly reduced survival probability compared to invasive breast carcinoma patients not expressing OR2W3. Furthermore, analysis of OR transcript abundance levels among 56 human breast cancer cell lines showed that 3 ORs (OR2A7, OR2B6, OR2W3) were exclusively upregulated in one cell group with 2, 1.3 and 2.1-fold increase compared to their upregulation levels in a human mammary epithelial cell line (MCF10A). The cell group with significant upregulation of OR2W3 was composed of 83% TNBC cell lines. These results show a consistent elevated upregulation of the OR2W3 gene in all the invasive breast tumors and cell lines. Our ongoing discovery research suggests that OR2W3 may be an indicator of breast cancer invasion. It is also possible that OR2W3 has signaling or other mechanistic roles in breast cancer progression, metastasis and reduced survival.
Citation Format: Shirin Masjedi, Laurence J. Zwiebel, Todd D. Giorgio. Characterization of olfactory receptor upregulation in invasive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3541.