DownregulatedofMTA3inERnegativeBreastTumors

Approximately 30% of breast carcinomas lack ER expression. Presumably, these breast cancers become estrogen independent through genetic alterations that bypass the requirement for ER-dependent stimulation of cell proliferation. As such estrogen receptor is a key regulator of proliferation and differentiation in mammary epithelia and represents a crucial prognostic indicator and therapeutic target in breast cancer. Mechanistically, estrogen receptor induces changes in gene expression through direct gene activation of a number of genes (cathepsin D, HSP27 (heat shock protein 27,000 kDa, aldolase A, dehydrogenase, alpha-tubulin, and glyceraldehyde-3-phosphat, Pdzk1, Greb ets) and also through the biological functions of target loci. The product of human MTA3 has been identified as an estrogen-dependent component of the Mi-2/NuRD transcriptional corepressor in breast epithelial cells and demonstrate that MTA3 constitutes a key component of an estrogen-dependent pathway regulating growth and differentiation. The absence of estrogen receptor or of MTA3 leads to aberrant expression of the transcriptional repressor Snail, a master regulator of epithelial to mesenchymal transitions. Aberrant Snail expression results in loss of expression of the cell adhesion molecule E-cadherin, an event associated with changes in epithelial architecture and invasive growth. MTA3 is the mechanistic link between estrogen receptor status and invasive growth of breast cancers.

Contributor: Kosi Gramatikoff, PhD

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