Molecular effects of oestrogen deprivation in breast cancer

Abstract

This paper reviews the effects of oestrogen deprivation by third generation aromatase inhibitors on molecular profiles in breast cancers. It particularly focuses on results obtained as a result of pre-operative and neoadjuvant therapy in which primary breast cancers have been biopsied or excised before and during treatment with letrozole, anastrozole or exemestane. Studies may be subdivided into those evaluating early (10-14 days) or late (3-4 months) changes; a single investigation charted sequential changes. Early changes involved downregulation of genes classically induced by oestrogen or associated with cell cycle and proliferation. In contrast, expressions of genes associated with stromal signatures were upregulated. Considerably more genes were changed at later time-points; these probably represent not only primary effects on cellular expression but secondary consequences of cell death and clonal selection. Thus, after 3-4 months of treatment mitochondrial-related genes and those associated with cell cycle and cell division were downregulated whereas genes associated with extracellular matrix (ECM) remodelling, vascularization, inflammatory responses and cell adhesion were upregulated. Recently, observations have been reported from a study in which tumours were sequentially sampled to include pretreatment and both early and later time-points. This allowed direct monitoring of the dynamic changes in gene expression. Different patterns of changes in gene expression were identified which were also associated with general differences in sub-cellular distribution of corresponding proteins. The effect of treatment on expression of specific genes and processes such as aromatase, oestrogen receptor (ER), oestrogen-regulated genes, HER2, p53, ribosomal proteins, markers of proliferation, oxidative phosphorylation and stromal response are summarized.