Differential Regulation and Targeting of Estrogen Receptor α Turnover in Invasive Lobular Breast Carcinoma
| Autor: | Ahmed Basudan, Kevin M. Levine, Rachel C. Jankowitz, Matthew J. Sikora, David N. Boone, Dorothy Carter, Jian Chen, Adrian V. Lee, David J. Dabbs, Jennifer M. Atkinson, Carolin Meier, Priscilla F. McAuliffe, Steffi Oesterreich, Nilgun Tasdemir, Sreeja Sreekumar |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Estrogen receptor Breast Neoplasms Biology 03 medical and health sciences 0302 clinical medicine Endocrinology Breast cancer Internal medicine Cell Line Tumor medicine Humans Neoplasm Invasiveness skin and connective tissue diseases Research Articles Messenger RNA Estradiol Cell growth Carcinoma Ductal Breast Estrogen Receptor alpha Ubiquitination medicine.disease body regions Gene Expression Regulation Neoplastic Carcinoma Lobular 030104 developmental biology Cell culture 030220 oncology & carcinogenesis Invasive lobular carcinoma Proteolysis Cancer research MCF-7 Cells Female Estrogen receptor alpha Protein Processing Post-Translational Invasive Lobular Breast Carcinoma |
| Zdroj: | Endocrinology |
| ISSN: | 1945-7170 |
| Popis: | Invasive lobular breast carcinoma (ILC) accounts for 10% to 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 < 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 2 selective estrogen receptor downregulators (SERDs), ICI 182,780 and AZD9496, on ERα turnover and cell growth. While ICI 182,780 and AZD9496 showed similar effects in IDC cells, in ILC cell lines, AZD9496 was not as effective as ICI 182,780 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. |
| Databáze: | OpenAIRE |
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