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Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy

Tengfei Xiao1,2, Wei Li1,3,4,5,6, Xiaoqing Wang1,2

  • 1Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215.

Proceedings of the National Academy of Sciences of the United States of America
|July 11, 2018
PubMed

Insights

Estrogen receptor-positive breast cancer resistance is linked to low C-terminal SRC kinase (CSK) levels, which activate p21-activated kinase 2 (PAK2) and promote tumor growth. Targeting PAK2 may overcome endocrine therapy resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Endocrine therapy resistance is a major challenge in advanced estrogen receptor-positive (ER+) breast cancer.
  • The mechanisms underlying this resistance are not fully understood.
  • Estrogen receptor-targeted therapies can lose efficacy over time.

Purpose of the Study:

  • To identify key molecular mechanisms driving endocrine therapy resistance in ER+ breast cancer.
  • To investigate the role of C-terminal SRC kinase (CSK) in regulating ER+ breast cancer growth and therapy response.
  • To explore potential therapeutic strategies targeting identified resistance pathways.

Main Methods:

  • Analysis of CSK expression in ER+ breast cancer models and patient samples.
  • Investigating the regulatory relationship between estrogen, CSK, and p21 protein-activated kinase 2 (PAK2) activation.
  • Assessing the impact of CSK levels on estrogen-independent tumor growth.
  • Evaluating the efficacy of combining a PAK2 inhibitor with an estrogen receptor (ER) antagonist in preclinical models.

Main Results:

  • Estrogen directly upregulates CSK expression in ER+ breast cancer.
  • Low CSK levels, observed in resistant tumors, lead to PAK2 activation.
  • Activated PAK2 drives estrogen-independent growth and is associated with poor clinical outcomes.
  • Combination therapy with a PAK2 inhibitor and an ER antagonist synergistically suppressed tumor growth.

Conclusions:

  • CSK functions as a critical negative regulator in an estrogen-induced feedback loop that limits ER-targeted therapy efficacy.
  • Loss of this feedback loop due to low CSK levels contributes to endocrine therapy resistance.
  • PAK2 activation is a key driver of resistance, and targeting PAK2 offers a promising strategy for overcoming resistance in ER+ breast cancer.
  • Clinical strategies should aim to restore or bypass this lost negative feedback loop.
Keywords:
CRISPR screenCSKbreast cancerendocrine resistanceestrogen receptor

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