Stopping treatment can reverse acquired resistance to letrozole.

Using the intratumoral aromatase xenograft model, we have observed that despite long-lasting growth inhibition, tumors eventually begin to grow during continued letrozole treatment. In cells isolated from these long-term letrozole-treated tumors (LTLT-Ca), estrogen receptor-alpha (ERalpha) levels were decreased, whereas signaling proteins in the mitogen-activated protein kinase cascade were up-regulated along with human epidermal growth factor receptor 2 (Her-2). In the current study, we evaluated the effect of discontinuing letrozole treatment on the growth of letrozole-resistant cells and tumors. The cells formed tumors equally well in the absence or presence of letrozole and had similar growth rates. After treatment was discontinued for 6 weeks, letrozole was administered again. Marked tumor regression was observed with this second course of letrozole treatment. Similarly, in MCF-7Ca xenografts, a 6-week break in letrozole treatment prolonged the responsiveness of the tumors to letrozole. To understand the mechanisms of this effect, LTLT-Ca cells were cultured in the absence of letrozole for 16 weeks. The resulting cell line (RLT-Ca) exhibited properties similar to MCF-7Ca cells. The cell growth was inhibited by letrozole and stimulated by estradiol. The expression of phosphorylated mitogen-activated protein kinase (MAPK) was reduced and ERalpha and aromatase levels increased compared with LTLT-Ca cells and were similar to levels in MCF-7Ca cells. These results indicate that discontinuing treatment can reverse letrozole resistance. This could be a beneficial strategy to prolong responsiveness to aromatase inhibitors for patients with breast cancer.
AuthorsGauri J Sabnis, Luciana F Macedo, Olga Goloubeva, Adam Schayowitz, Angela M H Brodie
JournalCancer research (Cancer Res) Vol. 68 Issue 12 Pg. 4518-24 (Jun 15 2008) ISSN: 1538-7445 [Electronic] United States
PMID18559495 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Antineoplastic Agents, Hormonal
  • Aromatase Inhibitors
  • Estrogen Receptor Modulators
  • Estrogen Receptor alpha
  • Nitriles
  • Triazoles
  • estrogen receptor alpha, human
  • Estradiol
  • letrozole
  • Aromatase
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Mitogen-Activated Protein Kinases
  • Animals
  • Antineoplastic Agents, Hormonal (therapeutic use)
  • Aromatase (chemistry, metabolism)
  • Aromatase Inhibitors (therapeutic use)
  • Breast Neoplasms (drug therapy, metabolism, pathology)
  • Cell Proliferation
  • Drug Resistance, Neoplasm
  • Estradiol (metabolism)
  • Estrogen Receptor Modulators (therapeutic use)
  • Estrogen Receptor alpha (metabolism)
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinases (metabolism)
  • Neoplasms, Hormone-Dependent (drug therapy, metabolism, pathology)
  • Nitriles (therapeutic use)
  • Ovariectomy
  • Phosphorylation (drug effects)
  • Receptor, ErbB-2 (metabolism)
  • Triazoles (therapeutic use)
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

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