Abstract 3791: PGRMC1 expression is significantly up-regulated in triple negative breast cancer in vivo with associated activation of cyclin D1 target genes: Analysis of 1019 invasive breast cancers in the TCGA database
Authors: McDonald Elizabeth S. , Zeng Chenbo , Mankoff David A. , Kossenkov Andrew , Mach Robert H. 
Published: August 2015

Background: A major gap in our understanding of cancer biology and treatment is how subpopulations of tumor cells escape chemotherapeutic toxicity. One mechanism of resistance is for a cancer cell to temporarily stop proliferating and enter the G0 or dormant phase of the cell cycle. The sigma-2 receptor (s2R) is expressed at different levels in both proliferating and dormant tumor cells, and as such holds great potential for imaging both proliferation and dormancy for the goal of identifying therapeutic response and resistance. Mach and colleagues have validated s2R imaging compounds as receptor-based biomarkers of tumor proliferation in vitro. s2R is a binding site on progesterone receptor membrane component 1 (PGRMC1), but little is known about its expression in breast cancer. The goal of this study was to explore expression of PGRMC1 in normal breast tissue and breast cancer, as a whole and stratified by tumor subtype to provide more information about the role of s2R in breast cancer.

Methods: The TCGA database was queried for invasive breast cancers with available RNA sequencing data (RNA Seq V2 RSEM). In total, data was available from 1019 invasive breast cancers: 738 ER+, 215 ER-, 643 PR+, 307 PR-, 149 HER2+, 508 HER2-, 102 TNBC. PGRMC1 expression was compared between all groups and plotted according to subtype. mRNA expression was tested for correlation with 20,531 genes and 461 genes correlating with PGRMC1 (Pearson r&gt;0.25, p&lt;10−15) within tumor samples were identified. A heatmap of expression levels for the top positively and negatively correlated genes was generated. These were then analyzed for enrichment of pathways, functions, networks, and upstream regulators using Ingenuity Pathway Analysis. The analysis was done using functions from Matlab R2012b.

Results: PGRMC1 mRNA expression was significantly upregulated in TNBC compared to both normal tissue (1.3 fold; p = 6 × 10−6) and other breast cancer subtypes (1.33 fold; p = 6 × 10−11). Additionally, direction of changes of target genes for regulators suggested activation of cyclin D1 (CCND1, z = 2.45, p = 8 × 10−5) and Myc (z = 1.95, p = 1 × 10−6), and inhibition of RICTOR (z = -4, p = 5 × 10−5) when PGRMC1 was more expressed. Measurement of mRNA levels of cyclin D1 demonstrated that expression was negatively correlated with PGRMC1, despite target gene activation with an average Pearson r = -0.22.

Conclusion: PGRMC1, the target of a putative novel marker of cancer cell proliferation and resistance, is upregulated in TNBC compared to normal breast tissue and other tumor subtypes and this is associated with cyclin D1 target gene activation and RICTOR target gene inhibition. These data demonstrate differential expression of s2R in breast cancer and an association between s2R and key cell cycle markers.

Citation Format: Elizabeth S. McDonald, Chenbo Zeng, David A. Mankoff, Andrew Kossenkov, Robert H. Mach. PGRMC1 expression is significantly up-regulated in triple negative breast cancer in vivo with associated activation of cyclin D1 target genes: Analysis of 1019 invasive breast cancers in the TCGA database. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3791. doi:10.1158/1538-7445.AM2015-3791