Masri S et al. - In a study to further elucidate mechanisms of acquired resistance to aromatase inhibitors (AI), these studies provide important information regarding differences in resistance mechanisms to AIs, TAM, and long-term estrogen deprived (LTEDaro), which are critical in overcoming resistance when treating hormone-responsive breast cancers Methods
MCF-7aro cells resistant to letrozole (T+LET R), anastrozole (T+ANA R), and exemestane (T+EXE R), as well as LTEDaro and tamoxifen-resistant (T+TAM R) lines were generated
Results
Microarray results clearly show that gene signatures unique to AI-resistance were inherently different from LTEDaro and T+TAM R gene expression profiles
Based on hierarchical clustering, unique estrogen-responsive gene signatures vary depending on cell line, with some genes up-regulated in all lines vs other genes up-regulated only in the AI-resistant lines
Characterization of these resistant lines showed that LTEDaro, T+LET R, and T+ANA R cells contained a constitutively active estrogen receptor (ER) that does not require estrogen for activation
This ligand-independent activation of ER was not observed in the parental cells, as well as T+EXE R and T+TAM R cells
Further characterization of these resistant lines was performed using cell cycle analysis, immunofluorescence experiments to visualize ER subcellular localization, as well as cross-resistance studies to determine second-line inhibitor response
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