Abstract P4-05-02: Differential regulation of ER protein-turnover in invasive lobular carcinoma cells
Authors: Jankowitz RC , Sreekumar S , Levine KM , Meier C , Sikora MJ , Basudan A , Boone D , Dabbs DJ , Jacobsen B , Lee AV , Oesterreich S 
Published: February 2018

Background: Invasive lobular breast carcinoma (ILC) accounts for 10-15% of breast cancers diagnosed annually. ILCs are more likely to be positive (90-95%) for ER compared to IDC (60-70%), and there is some evidence that endocrine treatment response might be different in patients with IDC vs ILC. We asked the question whether there were differences in ER protein steady state levels, and/or turn-over rates.

Methods: We utilized TCGA dataset to compare ESR1 mRNA and ER protein levels between ER+ ILC (n=137) and IDC (n=554). ER H-scores and ESR1 mRNA levels were analyzed from patients with ER+ ILC (n=143) and IDC (n=877) seen at UPMC Magee Women's Hospital. Correlation analysis with Pearson's (r) and Spearman's rank order coefficient (ρ) was used to study the relationship between mRNA and protein levels. Basal and ligand induced ESR1 mRNA and ER protein expression and turn-over were determined in a panel of estrogen responsive ER+ IDC (MCF-7, T47D and ZR75-1) and ILC (BCK-4, MDA-MB-134 VI (MM134), SUM44PE) cell lines to identify potential mechanisms that can contribute to differential expression of ERα protein.

Results: TCGA database analysis revealed significantly lower ESR1 mRNA and ER protein levels in ER+ ILC compared to IDC tumors. Analysis of data from our Magee hospital showed similar ER IHC H-scores for ER+ ILCs and IDCs despite having significantly lower ESR1 mRNA in ILC. In both the study sets, the correlation between ER mRNA and protein levels were found to be significantly weaker in ER+ ILC than IDC suggesting subtype specific increased synthesis and/or stability of the receptor protein. ILC cell lines MM134 and SUM44 have increased levels of ER protein compared to IDC cell lines. Estradiol decreased the levels and half-life of ER protein in all IDC cell lines tested. In MM134 and SUM44PE ILC cell lines, estradiol decreased the rate of degradation of ER and increased its half-life. In MM134 cells, treatment with estradiol induced a dose- and time-dependent increase in ER, which is associated with a sustained level of elevated phosphorylation at Ser 118.

Conclusions and ongoing/future studies: The estradiol-induced ER protein stability in a subset of ILC cell lines suggest a possible mechanism leading to weaker ER mRNA-protein correlation in ILC tumors. We currently do not know if and how this observation might be linked to antiestrogen response in ILC. We have recently initiated a TBCRC-supported trial in which we will compare the effect of different endocrine therapies in patients with ILC. Access to pre and post therapy samples will provide the opportunity to study ER levels and its downstream signaling as a function of antiestrogen treatment.

Citation Format: Jankowitz RC, Sreekumar S, Levine KM, Meier C, Sikora MJ, Basudan A, Boone D, Dabbs DJ, Jacobsen B, Lee AV, Oesterreich S. Differential regulation of ER protein-turnover in invasive lobular carcinoma cells [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-05-02.