1058 Loss of estrogen receptor in human breast cancer cells is associated with an epithelial to mesenchymal transition

Luqmani, Y.A.; Al-Mulla, Fahd; Azmi, A.

doi:10.1016/s1359-6349(09)70351-9

Cited by 1 publication

(5 citation statements)

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“…Significantly, in one of the first demonstrations of tumour related EMT in vivo, spontaneous up-regulation of sNAIL was associated with the recurrence of tumours with EMT characteristics in a reversible ERBB2-induced mouse breast cancer model (182). Loss of ER reduces MTA3 mediated inhibition of sNAIL hence promoting EMT (191). however, like sNAIL, the expression of sNAIL2 has been associated with poor clinical outcome in breast tumours (183).…”

Section: Epithelial To Mesenchymal Transitionmentioning

confidence: 99%

“…All of these studies indicate that AXL is a unique EMT effector that is essential for breast cancer progression (186). Endocrine-resistant breast cancer cells show highly elevated expression of AXL (191).…”

Section: Epithelial To Mesenchymal Transitionmentioning

confidence: 99%

“…however, N-cadherin ectopic expression also promotes motility, invasion and metastasis in E-cadherin-positive breast cancer cells (189) possibly in synergy with FGF2 (190) without impacting on their epithelial phenotype, suggesting that the malignant functions of N-cadherin are dominant over E-cadherin and pointing to EMT-independent routes to metastasis. Interestingly, the association of cadherin switching, in ER-targeting shRNA transfected MCF-7 cells, with increased motility reflected by membrane ruffling and F-actin rearrangement suggests that the loss of cellular adhesion molecules following acquisition of endocrine resistance is a major factor influencing the cells to move and invade into the surrounding tissues (191). The general role of cadherins has been extensively reviewed by Berx and van Roy (192).…”

Section: Epithelial To Mesenchymal Transitionmentioning

confidence: 99%

“…These cells have constitutively down-regulated ER, exhibit a higher proliferative rate, increased aggressive behaviour reflected by accelerated motility and ability to penetrate into simulated extracellular matrix components, co-incident with a change from an epithelial morphology to a more mesenchymal one (191,276). Rearrangement in these cells of the α-actin cytoskeleton reflects increased appearance of lamellipodia and microspikes, features known to drive cellular motility (277).…”

Section: Emt Cscs and Endocrine Resistancementioning

confidence: 99%

“…Another significant group that is elevated in these cells are included in the '24 gene signature' of genes proposed as predictive of invasiveness (278): integrin, TIMP-2 and TIMP-3, MT1-MMP, PAI-1, Osteonectin/sPARC, thrombospondin-1, collagen (VI) α1 and collagen (I) α2. A further interesting feature is the ability of various tyrosine kinase inhibitors to block proliferation, motility and invasion in these cells (191) reflecting an important role of peptide growth factor receptors, particularly EGFR. so far, all the experimental data are consistent with the view that in these cells that have acquired endocrine independence, there is an associated change that closely mimicks EMT.…”

Section: Emt Cscs and Endocrine Resistancementioning

confidence: 99%

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

Saleh

Sharaf²,

Luqmani

2011

Int J Oncol

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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...

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Section: Epithelial To Mesenchymal Transitionmentioning

confidence: 99%

Section: Epithelial To Mesenchymal Transitionmentioning

confidence: 99%