Abstract P1-21-03: Unique estrogen receptor alpha turnover, regulation and targeting in invasive lobular breast carcinoma
Authors: Jennifer M Atkinson, Sreeja Sreekumar, Kevin M Levine, Matthew J Sikora, Jian Chen, David J Dabbs, Carolin Meier, Ahmed Basudan, Nilgun Tasdemir, David Boone, Priscilla F McAuliffe, Rachel C Jankowitz, Adrian V Lee, Steffi Oesterreich
Journal: Cancer Research (2020)

Abstract Invasive lobular breast carcinoma (ILC) accounts for 10-15% of breast cancers diagnosed annually. Evidence suggests that endocrine treatment response might differ between invasive ductal carcinoma (IDC) and ILC, and that patients with ILC have worse long-term survival. ILCs are more likely to be estrogen receptor alpha (ER/ERα) positive (90-95%) compared to IDCs (60-70%). We investigated whether there are differences in ER protein steady state levels and/or turn-over rates in ILC that might explain differences in response to endocrine therapy. Analysis of the TCGA dataset revealed lower levels of ESR1 mRNA (P = 0.002) and ERα protein (P = 0.038) in ER+ ILC (n = 137) compared to ER+ IDC (n = 554). Supporting this observation, analysis of tumors from patients treated at UPMC Magee-Women’s Hospital (ILC, n = 143; IDC, n = 877), showed lower ESR1 mRNA (P &amp;lt; 0.005) in ILC and similar ERα protein levels in both subtypes. In both datasets, the correlation between ESR1 mRNA and ERα protein was significantly weaker in ILC suggesting differential post-transcriptional regulation of ER. This was confirmed in in vitro studies showing 17β-estradiol (E2) decreased the rate of degradation and increased half-life of ERα in MDA-MB-134-VI and SUM44PE ILC cell lines, whereas the opposite was observed in IDC cell lines. Further analysis of MDA-MB-134-VI cells revealed that E2 downregulated ubiquitination pathway genes and failed to induce ubiquitination of ERα. To determine potential clinical relevance of our findings, we evaluated the effect of two selective estrogen receptor down-regulators (SERDs) on ERα turnover and E2-induced proliferation of IDC and ILC cell lines. While fulvestrant and AZD9496, a novel orally bioavailable SERD, showed similar effects in IDC cell lines, AZD9496 was less effective than fulvestrant in decreasing ERα protein stability and E2-induced proliferation in ILC cells. Furthermore, AZD9496 exhibited partial agonist activity in growth and gene expression assays in the absence of ligand. Collectively, our data provide evidence for distinct ligand-induced ERα turnover in ILC cell lines. In addition, the novel SERD AZD9496 displays partial agonist activity in ILC cells, and further studies should address whether these observations are causally linked. These results provide a strong rationale for inclusion of ILC subgroups into preclinical and clinical testing of SERDs. Citation Format: Jennifer M Atkinson, Sreeja Sreekumar, Kevin M Levine, Matthew J Sikora, Jian Chen, David J Dabbs, Carolin Meier, Ahmed Basudan, Nilgun Tasdemir, David Boone, Priscilla F McAuliffe, Rachel C Jankowitz, Adrian V Lee, Steffi Oesterreich. Unique estrogen receptor alpha turnover, regulation and targeting in invasive lobular breast carcinoma [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-21-03.