Authors: Matthew J Sikora Viktoriya Strumba Marc E Lippman Michael D Johnson James M Rae
Publish Date: 2012/03/29
Volume: 134, Issue: 3, Pages: 1027-1039
Abstract
Despite the success of the aromatase inhibitors AIs in treating estrogen receptor positive breast cancer 15–20 of patients receiving adjuvant AIs will relapse within 5–10 years of treatment initiation Longterm estrogen deprivation LTED of breast cancer cells in culture mimics AIinduced estrogen depletion to dissect mechanisms of AI resistance However we hypothesized that a subset of patients receiving AI therapy may maintain low circulating concentrations of estrogens that influence the development of endocrine resistance We expanded established LTED models to account for incomplete suppression of estrogen synthesis during AI therapy MCF7 cells were grown in medium with charcoalstripped serum supplemented with defined concentrations of 17βestradiol E2 or the estrogenic androgen metabolite 5αandrostane3β17βdiol 3βAdiol an endogenous selective estrogen receptor modulator Cells were selected in concentrations of E2 or 3βAdiol that induce 10 or 90 percent of maximal proliferation EC10 and EC90 respectively or estrogen deprived Estrogen independence was evaluated during selection by assessing cell growth in the absence or presence of E2 or 3βAdiol Following 7 months of selection estrogen independence developed in estrogendeprived cells and EC10selected cells Functional analyses demonstrated that estrogendeprived and EC10selected cells developed estrogen independence via unique mechanisms ERαindependent and dependent respectively Estrogenindependent proliferation in EC10selected cells could be blocked by kinase inhibitors However these cells were resistant to kinase inhibition in the presence of low steroid concentrations These data demonstrate that further understanding of the total estrogen environment in patients on AI therapy who experience recurrence is necessary to effectively treat endocrineresistant diseaseThis study was supported in part by The Breast Cancer Research Foundation grant N003173 1R01 GM099143 and by T32 GM007767 from the National Institute of General Medical Sciences Bethesda MD We thank the University of Michigan DNA Sequencing Core Facility for technical assistance We also thank Dr Richard Santen for his helpful review of our manuscript
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