NDLI: Mechanisms of estrogen-independent breast cancer growth driven by low estrogen concentrations are unique versus complete estrogen deprivation

Content Provider	PubMed Central
Author	Sikora, Matthew J. Strumba, Viktoriya Lippman, Marc E. Johnson, Michael D. Rae, James M.
Copyright Year	2012
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. Long-term estrogen deprivation (LTED) of breast cancer cells in culture mimics AI-induced 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. MCF-7 cells were grown in medium with charcoal-stripped serum supplemented with defined concentrations of 17β-estradiol (E2) or the estrogenic androgen metabolite 5α-androstane-3β,17β-diol (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 estrogen-deprived cells and EC10-selected cells. Functional analyses demonstrated that estrogen-deprived and EC10-selected cells developed estrogen independence via unique mechanisms, ERα-independent and dependent, respectively. Estrogen-independent proliferation in EC10-selected 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 endocrine-resistant disease.
Related Links	http://dx.doi.org/10.1007/s10549-012-2032-6
Ending Page	1039
Page Count	13
Starting Page	1027
File Format	PDF
ISSN	01676806
e-ISSN	15737217
Journal	Breast cancer research and treatment
Issue Number	3
Volume Number	134
Language	English
Publisher Date	2012-08-01
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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