ZFIN ID: ZDB-PUB-210110-7
A feed-forward loop between SorLA and HER3 determines heregulin response and neratinib resistance
Al-Akhrass, H., Conway, J.R.W., Poulsen, A.S.A., Paatero, I., Kaivola, J., Padzik, A., Andersen, O.M., Ivaska, J.
Date: 2021
Source: Oncogene   40(7): 1300-1317 (Journal)
Registered Authors: Ivaska, Johanna, Paatero, Ilkka
Keywords: none
MeSH Terms:
  • Animals
  • Brain/drug effects
  • Brain/metabolism
  • Breast Neoplasms/genetics*
  • Breast Neoplasms/pathology
  • Cell Proliferation/drug effects
  • Drug Resistance, Neoplasm/drug effects
  • Drug Resistance, Neoplasm/genetics
  • Female
  • Heterografts
  • Humans
  • LDL-Receptor Related Proteins/genetics*
  • Membrane Transport Proteins/genetics*
  • Mice
  • Neuregulin-1/pharmacology
  • Receptor, ErbB-2/genetics*
  • Receptor, ErbB-3/genetics*
  • Spheroids, Cellular/drug effects
  • Spheroids, Cellular/metabolism
  • Zebrafish
  • rab4 GTP-Binding Proteins/genetics
PubMed: 33420373 Full text @ Oncogene
Current evidence indicates that resistance to the tyrosine kinase-type cell surface receptor (HER2)-targeted therapies is frequently associated with HER3 and active signaling via HER2-HER3 dimers, particularly in the context of breast cancer. Thus, understanding the response to HER2-HER3 signaling and the regulation of the dimer is essential to decipher therapy relapse mechanisms. Here, we investigate a bidirectional relationship between HER2-HER3 signaling and a type-1 transmembrane sorting receptor, sortilin-related receptor (SorLA; SORL1). We demonstrate that heregulin-mediated signaling supports SorLA transcription downstream of the mitogen-activated protein kinase pathway. In addition, we demonstrate that SorLA interacts directly with HER3, forming a trimeric complex with HER2 and HER3 to attenuate lysosomal degradation of the dimer in a Ras-related protein Rab4-dependent manner. In line with a role for SorLA in supporting the stability of the HER2 and HER3 receptors, loss of SorLA compromised heregulin-induced cell proliferation and sensitized metastatic anti-HER2 therapy-resistant breast cancer cells to neratinib in cancer spheroids in vitro and in vivo in a zebrafish brain xenograft model.