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Open Access 16-01-2024 | Estrogens | Original Laboratory Investigation

Endosomal recycling inhibitors downregulate estrogen receptor-alpha and synergise with endocrine therapies

Authors: Kelsey A. Fletcher, Mai H. Alkurashi, Andrew J. Lindsay

Published in: Breast Cancer Research and Treatment | Issue 3/2024

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Abstract

Purpose

Breast cancer (BC) accounts for roughly 30% of new cancers diagnosed in women each year; thus, this cancer type represents a substantial burden for people and health care systems. Despite the existence of effective therapies to treat BC, drug resistance remains a problem and is a major cause of treatment failure. Therefore, new drugs and treatment regimens are urgently required to overcome resistance. Recent research indicates that inhibition of the endosomal recycling pathway, an intracellular membrane trafficking pathway that returns endocytosed proteins back to the plasma membrane, may be a promising strategy to downregulate clinically relevant cell surface proteins such as HER2 and HER3, and to overcome drug resistance.

Methods

To investigate the molecular mechanism of action of an endosomal recycling inhibitor (ERI) called primaquine, we performed a reverse-phase protein array (RPPA) assay using a HER2-positive breast cancer cell line. The RPPA findings were confirmed by Western blot and RT-qPCR in several BC cell lines. Novel drug combinations were tested by MTT cell viability and clonogenic assays.

Results

Among the signalling molecules downregulated by ERIs were estrogen receptor-alpha (ER-α) and androgen receptor. We confirmed this finding in other breast cancer cell lines and show that downregulation occurs at the transcriptional level. We also found that ERIs synergise with tamoxifen, a standard-of-care therapy for breast cancer.

Discussion

Our data suggest that combining ERIs with hormone receptor antagonists may enhance their efficacy and reduce the emergence of drug resistance.
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Metadata
Title
Endosomal recycling inhibitors downregulate estrogen receptor-alpha and synergise with endocrine therapies
Authors
Kelsey A. Fletcher
Mai H. Alkurashi
Andrew J. Lindsay
Publication date
16-01-2024
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 3/2024
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-023-07225-2

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