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Oestrogen Non-Genomic Signalling is Activated in Tamoxifen-Resistant Breast Cancer

Coralie Poulard1,2,3, Julien Jacquemetton4,5,6, Olivier Trédan7,8,9,10

  • 1Université de Lyon, F-69000 Lyon, France. coralie.poulard@lyon.unicancer.fr.

International Journal of Molecular Sciences
|June 15, 2019
PubMed

Insights

Oestrogen receptor alpha (ERα) interactions with Src and PI3K increase in tamoxifen-resistant breast cancer. Inhibiting ERα-Src interactions may restore tamoxifen sensitivity, offering new therapeutic strategies for endocrine resistance.

Area of Science:

  • Oncology
  • Endocrinology
  • Molecular Biology

Background:

  • Endocrine therapies targeting oestrogen signalling are crucial for ERα-positive breast cancer.
  • Treatment resistance remains a significant clinical challenge, limiting therapeutic efficacy.
  • Non-genomic oestrogen signalling via the ERα/Src/PI3K complex is implicated in aggressive breast cancer.

Purpose of the Study:

  • To investigate the role of ERα/Src/PI3K pathway activation in endocrine therapy resistance.
  • To determine if ERα interactions with Src and PI3K are altered in tamoxifen-resistant breast cancer models.
  • To explore the therapeutic potential of targeting ERα-Src interactions to overcome resistance.

Main Methods:

  • Proximity Ligation Assay (PLA) to study ERα interactions with Src and PI3K.
  • Utilized in vitro (MCF-7 cells) and in vivo (patient-derived xenografts) models of tamoxifen resistance.
  • Tested a peptide inhibitor targeting the ERα-Src interaction.

Main Results:

  • Increased ERα/Src and ERα/PI3K interactions were observed in tamoxifen-resistant breast cancer models (MCF-7 cells and PDXs).
  • These specific interactions were not elevated in resistance to other endocrine therapies.
  • A peptide inhibiting ERα-Src interaction partially restored sensitivity to tamoxifen in resistant cells.

Conclusions:

  • Activation of ERα/Src and ERα/PI3K signalling pathways is associated with acquired tamoxifen resistance in breast cancer.
  • The ERα-Src interaction represents a potential therapeutic target to circumvent tamoxifen resistance.
  • Targeting this pathway could offer novel strategies for managing endocrine-resistant breast cancer.
Keywords:
PDXbiomarkerbreast canceroestrogen non-genomic signallingresistance to endocrine therapy

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