Differential Regulation and Targeting of Estrogen Receptor α Turnover in Invasive Lobular Breast Carcinoma

Abstract

<jats:title>Abstract</jats:title> <jats:p>Invasive lobular breast carcinoma (ILC) accounts for 10-15% of breast cancers diagnosed annually. Evidence suggests that some aspects of endocrine treatment response might differ between invasive ductal carcinoma (IDC) and ILC, and that patients with ILC have worse long-term survival. We analyzed The Cancer Genome Atlas dataset and observed lower levels of ESR1 mRNA (P=0.002) and ERα protein (P=0.038) in ER+ ILC (n=137) compared to IDC (n=554) and further confirmed the mRNA difference in a local UPMC cohort (ILC, n=143; IDC, n=877; P&amp;lt;0.005). In both datasets, the correlation between ESR1 mRNA and ERα protein was weaker in ILC suggesting differential post-transcriptional regulation of ERα. In vitro, 17β-estradiol (E2) decreased the rate of degradation and increased the half-life of ERα in ILC cell lines, whereas the opposite was observed in IDC cell lines. Further, E2 failed to induce robust ubiquitination of ERα in ILC cells. To determine the potential clinical relevance of these findings, we evaluated the effect of two selective estrogen receptor down-regulators (SERDs), ICI182,780 and AZD9496, on ERα turnover and cell growth. While ICI182,780 and AZD9496 showed similar effects in IDC cells, in ILC cell lines, AZD9496 was not as effective as ICI182,780 in decreasing ERα stability and E2 induced proliferation. Furthermore, AZD9496 exhibited partial agonist activity in growth assays in ILC cell lines. Our study provides evidence for a distinct ERα regulation by SERDs in ILC cell lines and therefore it is important to include ILC models into preclinical and clinical testing of novel SERDs.</jats:p>

Mediator of DNA damage checkpoint 1 (MDC1) is a novel estrogen receptor co-regulator in invasive lobular carcinoma of the breast

“…Future studies will examine differential MDC1 PTM in ILC versus IDC contexts. Differential MDC1 PTM as a mechanism to facilitate ER interaction may parallel our recent findings that ER protein is differentially regulated in ILC cells, showing reduced ligand-driven ubiquitination and degradation versus ER in IDC cells [16].…”

“…Poor outcomes and tamoxifen resistance were also reported for the ABCSG-8 trial [11]. Paralleling clinical data, we and others find ER+ ILC models are tamoxifen-resistant, including de novo ER partial agonism by anti-estrogens, including both tamoxifen and oral selective ER degraders [12][13][14][15][16]. Further, in cell line and in vivo ILC models, we found ER regulates hundreds of unique target genes via distinct ER DNA binding [12], and that ER regulates novel signaling pathways critical for endocrine response and resistance in ILC, such as cell-intrinsic Wnt signaling via WNT4 [12,[17][18][19].…”

Estrogen Regulation of mTOR Signaling and Mitochondrial Function in Invasive Lobular Carcinoma Cell Lines Requires WNT4

“…Consistent with clinical observations, we identified tamoxifen-resistance in ER-positive ILC models, including de novo ER partial agonism by anti-estrogens [ 14 , 15 ], tamoxifen-resistance is driven by diverse mechanisms across ILC models [ 16 , 17 , 18 ]. Further, we recently reported that post-transcriptional regulation of ER and protein turnover in response to ligand binding is distinct in ILC cells [ 19 ]. These data suggest that ER function and signaling is unique in the context of ILC.…”

Structural and functional analysis of female sex hormones against SARS-Cov2 cell entry

“…We extend these in silico observations by also demonstrating that entry of the S-RBD can be augmented in vitro by exposure of cultured HUVECs to a hyperglycemic environment that increases ACE2 glycosylation. These observations provide insights into the enhanced susceptibility of diabetic patients to severe infections and death in COVID-19 [30][31][32] .…”