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Review
. 2012 Jul-Aug;3(4):165-70.
doi: 10.4161/trns.20496. Epub 2012 Jul 1.

Endocrine resistance in breast cancer: from cellular signaling pathways to epigenetic mechanisms

Stéphanie Bianco  1 , Nicolas Gévry
Affiliations
Review

Endocrine resistance in breast cancer: from cellular signaling pathways to epigenetic mechanisms

Stéphanie Bianco et al. Transcription. 2012 Jul-Aug.

Abstract

Although multiple cellular mechanisms have been proposed to explain endocrine resistance in breast cancer, the genomics events promoting the dysregulation of gene expression pattern are not clearly understood. Because chromatin plays a dynamic role in the estrogen receptor α (ERα) transcriptional program, we herein review signaling pathways implicated in endocrine resistance and try to merge them with recent epigenetic studies.

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Figure 1. Molecular mechanisms in endocrine resistance. De novo resistance in breast cancer is characterized by loss of ERα expression and CYP2D6 deficiency that reduces tamoxifen to be metabolized into the active metabolite 4-hydroxytamoxifen (OH-TAM). Acquired resistance to AE involves alteration in signal transduction mediated by increased expression and/or activity of receptor tyrosine kinase family members such as HER2, EGFR and IGFR or G coupled-protein receptor GPR30. These events result in aberrant activation of downstream signaling pathways including cAMP/PKA, MAPK/ERK and PI3K/AKT. These activated kinases drive the phosphorylation of ERα and some of its coactivators, such as AIB1, MED1 or CARM1, which are responsible for constitutive ERα-mediated transcription and inhibition of AE effects on proliferation and apoptosis gene targets. Dysregulation of miRNA transcription is also involved in AE resistance. At the genomic level, substitution of canonical histones with the histone variant H2A.Z, or modification of DNA and histone methylation levels, exert an important influence on gene transcription. Pioneer factors FOXA1 and PBX1 drive ERα recruitment to specific genomic sites. In AE-resistance, the binding profile of these factors is often altered, resulting in aberrant ERα cistrome and gene expression program.
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