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PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast

Ana Bosch1, Zhiqiang Li1, Anna Bergamaschi2

  • 1Human Oncology and Pathogenesis Program and Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.

Science Translational Medicine
|April 17, 2015
PubMed

Insights

Activating PIK3CA mutations drive ER-positive breast cancer. PI3Kα inhibitors can increase estrogen receptor (ER) activity, limiting treatment effectiveness. Combining PI3K and ER inhibition shows promise for improved tumor regression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Activating PIK3CA mutations are common in ER-positive breast cancer.
  • Selective PI3Kα inhibitors are under clinical investigation for these tumors.
  • Response to PI3Kα inhibitors is variable, suggesting resistance mechanisms.

Purpose of the Study:

  • To investigate mechanisms of resistance to PI3Kα inhibitors in ER-positive breast cancer.
  • To explore the interplay between PI3K signaling and estrogen receptor (ER) activity.
  • To evaluate combination therapy strategies involving PI3K and ER inhibition.

Main Methods:

  • Analysis of gene expression changes upon PI3K inhibition.
  • Assessment of ER binding to gene promoter regions.
  • In vivo studies using xenografts and patient-derived models.
  • Evaluation of combination therapy with anti-ER agents (fulvestrant, tamoxifen).

Main Results:

  • PI3K inhibition induces ER-dependent transcriptional activity and increases ER expression.
  • These effects were confirmed in preclinical models and patient tumors treated with BYL719.
  • Estradiol enhanced ER transcriptional activity, while fulvestrant and tamoxifen suppressed it.
  • Fulvestrant combined with PI3Kα inhibition led to significant tumor regression in vivo.

Conclusions:

  • Increased ER transcriptional activity is a potential resistance mechanism to PI3Kα inhibitors.
  • Combined PI3K and ER inhibition represents a rational therapeutic strategy for PIK3CA-mutant ER-positive breast cancer.
  • Targeting both pathways may overcome resistance and improve treatment outcomes.

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