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Updated: Dec 6, 2025

An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation
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An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation

Published on: June 30, 2015

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CD44/HA signaling mediates acquired resistance to a PI3Kα inhibitor

Cuixia Yang1,2, Yumeng Sheng1, Xiaoxing Shi3

  • 1Department of Molecular Biology Laboratory, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233, Shanghai, China.

Cell Death & Disease
|October 7, 2020
PubMed

Insights

Luminal breast cancers develop resistance to PI3Kα inhibitors via an ER-CD44-HA signaling circuit. This pathway reactivates Src-ERK signaling, maintaining cancer cell survival and drug resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Luminal breast cancer (BrCa) with PIK3CA mutations often responds initially to phosphoinositide-3-kinase (PI3K)-α inhibitors.
  • Acquired resistance to these inhibitors is a significant clinical challenge, with underlying mechanisms poorly understood.

Purpose of the Study:

  • To elucidate the mechanisms of adaptive resistance to PI3Kα inhibitors in luminal BrCa.
  • To identify potential therapeutic targets to overcome this resistance.

Main Methods:

  • Investigated adaptive resistance mechanisms in luminal BrCa models treated with a PI3Kα inhibitor (BLY719).
  • Analyzed the role of CD44 splicing, estrogen receptor (ER) activity, and hyaluronan (HA) interaction in resistance.
  • Examined the involvement of Src-ERK and AKT/mTOR signaling pathways.

Main Results:

  • Acquired resistance was associated with a CD44-high state driven by aberrant splicing.
  • CD44 expression correlated with ER activity, mediating ER-dependent transcription under PI3Kα inhibition.
  • CD44/hyaluronan interaction activated Src-ERK signaling, sustaining AKT/mTOR activity and conferring resistance.
  • Disrupting the CD44/HA interaction restored sensitivity to the PI3Kα inhibitor.

Conclusions:

  • An ER-CD44-HA signaling axis promotes adaptive resistance to PI3Kα inhibitors in luminal breast cancer.
  • This circuit drives compensatory Src-ERK activation, maintaining pathway signaling despite PI3Kα inhibition.
  • Targeting the CD44/HA interaction presents a potential strategy to overcome resistance to PI3Kα inhibitors.

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