Signalling pathways involved in endocrine resistance in breast cancer and associations with epithelial to mesenchymal transition (Review)

Abstract

Abstract. Both de novo and acquired endocrine resistance constitute a major therapeutic problem for treatment of hormone-positive breast cancer. Multiple explanatory mechanisms have been proposed through the study of cellular models which focus principally on receptor tyrosine kinase mediated signalling pathways utilizing sRC, PI3K, MAPK and sMAds. Many of the transducing molecules, particularly nuclear transcription factors such as sNAIL, TwIsT, sNAIL2, ZEB, FOXC2, TCF/LEF and GOOsECOId are participants in proliferation as well as invasion and metastasis, involving a process of orchestrated cellular remodeling which is being likened to the process of epithelial to mesenchymal transition that takes place during embryonic development. we review the accumulating evidence that points towards the occurrence of this phenomenon as a consequence of the loss of endocrine control, with both processes being similarly characterized by depletion of cell adhesion proteins, E-cadherin, catenins and cytokeratins, increased association with the extracellular matrix through induction of metalloproteinases, fibronectin and collagen, and a switch to a mobile vimentin-based cytoskeletal structure with loss of apical basal polarity. IntroductionEndocrine therapy represents the most effective form of treatment for the majority of breast cancer patients whose tumours over-express the estrogen receptor (ER). In addition to ablative procedures (ovariectomy) and administration of antiendocrine agents to inhibit ovarian function, treatment is reliant predominantly upon anti-hormonal agents termed selective estrogen modulators (sERMs). Until recent introduction of agents such as toremifene and raloxifene, tamoxifen has been the mainstay of treatment (1) inducing objective response or disease stabilization in over half of previously untreated metastatic breast cancer patients with ER + tumours (2). Further options include the use of pure anti-estrogens such as fulvestrant (Faslodex) which achieves its effects through receptor degradation, and application of aromatase inhibitors that reduce extra-gonadal peripheral estrogen synthesis from the adrenals and adipose tissue, including the breast. Both types of agents improve relapse-free survival and reduce incidence of contralateral breast cancers in women with early-stage cancer and increase overall survival in patients with advanced disease (3,4). Unfortunately, following initial response to sERMs and second line therapy with aromatase inhibitors, most patients subsequently develop resistance to both classes of drugs and become refractive to further attempts at endocrine manipulation. Added to the de novo resistance in patients whose tumours express levels of ER <10 fmol/mg protein, this presents a serious therapeutic problem, particularly in view of the increased aggressiveness of hormone insensitive breast cancers. Estrogen receptor actionThe classical mode of action of ER is related to the regulation of expression of genes with estrogen response elements (ERE) in their promoters through t...

Metabotropic Glutamate Receptor 1 Expression and Its Polymorphic Variants Associate with Breast Cancer Phenotypes

“…In fact, the positive correlation between GRM1 expression and cell proliferation was confirmed in this study. Activation of GRM1 leads to increased MAPK and AKT activities where both are known to contribute to resistance to breast cancer endocrine therapies including tamoxifen [27], [28], [30], [56]-[59].…”

Mechanisms of Resistance to Endocrine Therapy in Breast Cancer: Focus on Signaling Pathways, miRNAs and Genetically Based Resistance

“…Other signal transduction pathways related to the endocrine resistance are nuclear factor-κB (NFκB), Notch, keratinocyte growth factor (KGF), and platelet-derived growth factor (PDGF)/Abl signaling pathway [152–154]. …”

“…It has also been found that the Notch pathway is implicated in both cell fate in the normal human mammary gland and regulation of cancer stem cells (CCs) in both ductal carcinoma in situ and invasive carcinoma of the breast [152,160,161]. Binding of Notch ligand (Jagged or Delta) to the Notch receptor cleaves its intracellular domain (NICD), which translocates to the nucleus where it binds with co-activators to induce transcription of its target genes and regulates migration and invasion of breast cancer cells.…”

When Good Turns Bad: Regulation of Invasion and Metastasis by ErbB2 Receptor Tyrosine Kinase

“…The molecular events controlling EMT and stemness of breast cancer cells are overlapping [161,162,163]. Tumor initiating, circulating tumor cells (CTC) have a central role in the metastatic spread.…”