Breast cancer is the second cause of cancer related death in women. High percentage of breast cancer tumours express estrogen receptors alpha (ERα) and beta (ERβ). Endocrine treatments for breast cancer that target ERα are effective, but acquired resistance is a limiting drawback.[1] One hypothesized mechanism of acquired resistance is the switch from ERα receptor to estrogen-related receptor α (ERRα) dependency. ERRα belongs to an orphan receptor family, including three members α, β, and γ, which bind to DNA sequences known as estrogen-response element (ERE) and estrogen related receptor response element (ERRE), promoting transcription of genes involved in endocrine-resistance.[2] Our studies focused on the evaluation of mevalonate and cholesterol activity to promote ERRα pathway and endocrine-resistance. We found that mevalonate and cholesterol treatment of MCF-7 wild type (WT) cells (sensible to endocrine therapy) deeply affected their glycolytic and oxidative profiles, shifting towards a like phenotype insensible to Tamoxifen (MCF-7/TAMR). We also evaluated expression levels of ERRα and ERbB2, usually not overexpressed in MCF-7 WT and implicated in tumour aggressiveness. Mevalonate or cholesterol treatment upregulated ERRα and ERbB2 levels, highlighting the activation of ERRα pathway and the dependency of treated cells on such receptors to obtain advantage in growth. Mitochondrial import receptor subunit TOM20, used as a mitochondrial marker, resulted upregulated after such treatments, suggesting an increased mitochondrial dimension or biogenesis. Besides, propagation of cancer-stem like cells (CSCs) after mevalonate or cholesterol treatments was significantly improved. Our results suggest that ERRα promotes endocrine resistance providing a rationale for its exploration as a candidate drug target to treat endocrine resistance.

ERRα PATHWAY AND ENDOCRINE RESISTANCE ON BREAST CANCER: CHOLESTEROL AND MEVALONATE INVOLVEMENT

Brindisi M.;Fiorillo M.;Frattaruolo L.;Curcio R.;Dolce V.;Cappello A. R.
2019

Abstract

Breast cancer is the second cause of cancer related death in women. High percentage of breast cancer tumours express estrogen receptors alpha (ERα) and beta (ERβ). Endocrine treatments for breast cancer that target ERα are effective, but acquired resistance is a limiting drawback.[1] One hypothesized mechanism of acquired resistance is the switch from ERα receptor to estrogen-related receptor α (ERRα) dependency. ERRα belongs to an orphan receptor family, including three members α, β, and γ, which bind to DNA sequences known as estrogen-response element (ERE) and estrogen related receptor response element (ERRE), promoting transcription of genes involved in endocrine-resistance.[2] Our studies focused on the evaluation of mevalonate and cholesterol activity to promote ERRα pathway and endocrine-resistance. We found that mevalonate and cholesterol treatment of MCF-7 wild type (WT) cells (sensible to endocrine therapy) deeply affected their glycolytic and oxidative profiles, shifting towards a like phenotype insensible to Tamoxifen (MCF-7/TAMR). We also evaluated expression levels of ERRα and ERbB2, usually not overexpressed in MCF-7 WT and implicated in tumour aggressiveness. Mevalonate or cholesterol treatment upregulated ERRα and ERbB2 levels, highlighting the activation of ERRα pathway and the dependency of treated cells on such receptors to obtain advantage in growth. Mitochondrial import receptor subunit TOM20, used as a mitochondrial marker, resulted upregulated after such treatments, suggesting an increased mitochondrial dimension or biogenesis. Besides, propagation of cancer-stem like cells (CSCs) after mevalonate or cholesterol treatments was significantly improved. Our results suggest that ERRα promotes endocrine resistance providing a rationale for its exploration as a candidate drug target to treat endocrine resistance.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11770/336086
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