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Endocrine therapy resistance can be associated with high estrogen receptor alpha (ERalpha) expression and reduced

Barbara Kuske1, Catherine Naughton, Kate Moore

  • 1CRUK Cancer Research Centre and Academic Breast Unit, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.

Endocrine-Related Cancer
|December 13, 2006
PubMed

Insights

Estrogen receptor (ER)-positive breast cancer cells can become resistant to endocrine therapies. High ERalpha expression drives growth even without estrogen, but blocking ERalpha still inhibits cancer cell proliferation.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cancer Research

Background:

  • Estrogen receptor (ER)-positive breast cancer cells can develop resistance to endocrine therapies like aromatase inhibitors.
  • This resistance often involves adaptation to low estrogen environments, leading to estrogen insensitivity but potential continued ER dependence.

Purpose of the Study:

  • To investigate the expression, function, and activation of ERalpha in endocrine-resistant breast cancer models (MCF-7/LCC1 and MCF-7/LCC9).
  • To identify mechanisms contributing to endocrine resistance and estrogen independence.

Main Methods:

  • Utilized two MCF-7 cell line models (MCF-7/LCC1 and MCF-7/LCC9) exhibiting varying degrees of estrogen resistance.
  • Assessed ERalpha expression, promoter binding, gene transcription (TFF1, progesterone receptor), cell growth inhibition via siRNA and fulvestrant, and ERalpha phosphorylation at Ser118 and Ser167.

Main Results:

  • High ERalpha expression was linked to increased binding to the TFF1 promoter and elevated TFF1 and progesterone receptor transcription, even without estrogen.
  • MCF-7/LCC9 cells showed full estrogen insensitivity and resistance to tamoxifen and fulvestrant.
  • While cells exhibited estrogen-independent growth, their proliferation was inhibited by ERalpha knockdown (siRNA) or fulvestrant, indicating ERalpha dependence.
  • Estrogen activated ERalpha Ser118 in MCF-7 and MCF-7/LCC1 cells, but not in the fully resistant MCF-7/LCC9 cells.

Conclusions:

  • Estrogen-independent growth in resistant cells is driven by high ERalpha expression levels.
  • Complete estrogen independence in MCF-7/LCC9 cells is associated with a lack of ERalpha activation via Ser118 phosphorylation.

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