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National Institute of Environmental Health Sciences

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Publication Detail

Title: HNRNPA2B1 regulates tamoxifen- and fulvestrant-sensitivity and hallmarks of endocrine resistance in breast cancer cells.

Authors: Petri, Belinda J; Piell, Kellianne M; South Whitt, Gordon C; Wilt, Ali E; Poulton, Claire C; Lehman, Norman L; Clem, Brian F; Nystoriak, Matthew A; Wysoczynski, Marcin; Klinge, Carolyn M

Published In Cancer Lett, (2021 Oct 10)

Abstract: Despite new combination therapies improving survival of breast cancer patients with estrogen receptor α (ER+) tumors, the molecular mechanisms for endocrine-resistant disease remain unresolved. Previously we demonstrated that expression of the RNA binding protein and N6-methyladenosine (m6A) reader HNRNPA2B1 (A2B1) is higher in LCC9 and LY2 tamoxifen (TAM)-resistant ERα breast cancer cells relative to parental TAM-sensitive MCF-7 cells. Here we report that A2B1 protein expression is higher in breast tumors than paired normal breast tissue. Modest stable overexpression of A2B1 in MCF-7 cells (MCF-7-A2B1 cells) resulted in TAM- and fulvestrant- resistance whereas knockdown of A2B1 in LCC9 and LY2 cells restored TAM and fulvestrant, endocrine-sensitivity. MCF-7-A2B1 cells gained hallmarks of TAM-resistant metastatic behavior: increased migration and invasion, clonogenicity, and soft agar colony size, which were attenuated by A2B1 knockdown in MCF-7-A2B1 and the TAM-resistant LCC9 and LY2 cells. MCF-7-A2B1, LCC9, and LY2 cells have a higher proportion of CD44+/CD24-/low cancer stem cells (CSC) compared to MCF-7 cells. MCF-7-A2B1 cells have increased ERα and reduced miR-222-3p that targets ERα. Like LCC9 cells, MCF-7-A2B1 have activated AKT and MAPK that depend on A2B1 expression and are growth inhibited by inhibitors of these pathways. These data support that targeting A2B1 could provide a complimentary therapeutic approach to reduce acquired endocrine resistance.

PubMed ID: 34273466 Exiting the NIEHS site

MeSH Terms: Adenosine/analogs & derivatives; Adenosine/metabolism; Breast Neoplasms/drug therapy*; Breast Neoplasms/metabolism*; CD24 Antigen/metabolism; Cell Line, Tumor; Endocrine Cells/metabolism*; Estrogen Receptor alpha/metabolism; Female; Fulvestrant/pharmacology*; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism*; Humans; Hyaluronan Receptors/metabolism; MCF-7 Cells; Neoplastic Stem Cells/metabolism; Signal Transduction/physiology; Tamoxifen/pharmacology*

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