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

Autor: Fletcher KA; Membrane Trafficking and Disease Laboratory, School of Biochemistry & Cell Biology, Biosciences Institute, University College Cork, Cork, T12 YT20, Ireland., Alkurashi MH; Membrane Trafficking and Disease Laboratory, School of Biochemistry & Cell Biology, Biosciences Institute, University College Cork, Cork, T12 YT20, Ireland., Lindsay AJ; Membrane Trafficking and Disease Laboratory, School of Biochemistry & Cell Biology, Biosciences Institute, University College Cork, Cork, T12 YT20, Ireland. a.lindsay@ucc.ie.
Jazyk: angličtina
Zdroj: Breast cancer research and treatment [Breast Cancer Res Treat] 2024 Apr; Vol. 204 (3), pp. 631-642. Date of Electronic Publication: 2024 Jan 16.
DOI: 10.1007/s10549-023-07225-2
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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