Endocrine resistance in breast cancer

Zheng, Lu; Zhao, Yang; Feng, Helian; Liu, Y. J.

doi:10.3109/13697137.2013.864268

Cited by 12 publications

(8 citation statements)

References 38 publications

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“…COL4 was absent from the tumor stroma, with only perivascular COL4 observed (Figure 1E ). Accompanying these changes in ECM composition, heterogeneous breast cancer microenvironments are enriched with hormones (Garcia-Robles et al, 2013 ; Simões et al, 2015 ), growth factors (Mimeault et al, 2007 ; Ye et al, 2009 ; Zheng et al, 2014 ; Ho-Yen et al, 2015 ; Voudouri et al, 2015 ), cytokines (Esquivel-Velazquez et al, 2015 ; Weichhaus et al, 2015 ), chemokines (Palacios-Arreola et al, 2014 ) and cell adhesion proteins (Spivey et al, 2012 ; Beauchemin and Arabzadeh, 2013 ; Karousou et al, 2014 ; Yu and Elble, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

Microenvironment-Induced Non-sporadic Expression of the AXL and cKIT Receptors Are Related to Epithelial Plasticity and Drug Resistance

Jokela

Engelsen

Rybicka

et al. 2018

Front. Cell Dev. Biol.

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The existence of rare cancer cells that sporadically acquire drug-tolerance through epigenetic mechanisms is proposed as one mechanism that drives cancer therapy failure. Here we provide evidence that specific microenvironments impose non-sporadic expression of proteins related to epithelial plasticity and drug resistance. Microarrays of robotically printed combinatorial microenvironments of known composition were used to make cell-based functional associations between microenvironments, which were design-inspired by normal and tumor-burdened breast tissues, and cell phenotypes. We hypothesized that specific combinations of microenvironment constituents non-sporadically impose the induction of the AXL and cKIT receptor tyrosine kinase proteins, which are known to be involved in epithelial plasticity and drug-tolerance, in an isogenic human mammary epithelial cell (HMEC) malignant progression series. Dimension reduction analysis reveals type I collagen as a dominant feature, inducing expression of both markers in pre-stasis finite lifespan HMECs, and transformed non-malignant and malignant immortal cell lines. Basement membrane-associated matrix proteins, laminin-111 and type IV collagen, suppress AXL and cKIT expression in pre-stasis and non-malignant cells. However, AXL and cKIT are not suppressed by laminin-111 in malignant cells. General linear models identified key factors, osteopontin, IL-8, and type VIα3 collagen, which significantly upregulated AXL and cKIT, as well as a plasticity-related gene expression program that is often observed in stem cells and in epithelial-to-mesenchymal-transition. These factors are co-located with AXL-expressing cells in situ in normal and breast cancer tissues, and associated with resistance to paclitaxel. A greater diversity of microenvironments induced AXL and cKIT expression consistent with plasticity and drug-tolerant phenotypes in tumorigenic cells compared to normal or immortal cells, suggesting a reduced perception of microenvironment specificity in malignant cells. Microenvironment-imposed reprogramming could explain why resistant cells are seemingly persistent and rapidly adaptable to multiple classes of drugs. These results support the notion that specific microenvironments drive drug-tolerant cellular phenotypes and suggest a novel interventional avenue for preventing acquired therapy resistance.

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Section: Resultsmentioning

confidence: 99%

Microenvironment-Induced Non-sporadic Expression of the AXL and cKIT Receptors Are Related to Epithelial Plasticity and Drug Resistance

Jokela

Engelsen

Rybicka

et al. 2018

Front. Cell Dev. Biol.

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“…We have previously shown that Notch signalling plays a significant role in the development of endocrine therapy resistance [ 18 , 19 , 29 , 30 ]. Notch signalling is partly dependent on the absolute amounts of Notch receptors present in the cells.…”

Section: Resultsmentioning

confidence: 99%

DMXL2 drives epithelial to mesenchymal transition in hormonal therapy resistant breast cancer through notch hyper-activation

et al. 2015

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The acquisition of endocrine therapy resistance in estrogen receptor α (ERα) breast cancer patients represents a major clinical problem. Notch signalling has been extensively linked to breast cancer especially in patients who fail to respond to endocrine therapy. Following activation, Notch intracellular domain is released and enters the nucleus where activates transcription of target genes. The numerous steps that cascade after activation of the receptor complicate using Notch as biomarker. Hence, this warrants the development of reliable indicators of Notch activity. DMXL2 is a novel regulator of Notch signalling not yet investigated in breast cancer. Here, we demonstrate that DMXL2 is overexpressed in a subset of endocrine therapy resistant breast cancer cell lines where it promotes epithelial to mesenchymal transition through hyper-activation of Notch signalling via V-ATPase dependent acidification. Following DMXL2 depletion or treatment with Bafilomycin A1, both EMT targets and Notch signalling pathway significantly decrease. We show for the first time that DMXL2 protein levels are significantly increased in ERα positive breast cancer patients that progress after endocrine therapy. Finally, we demonstrate that DMXL2 is a transmembrane protein with a potential extra-cellular domain. These findings identify DMXL2 as a novel, functional biomarker for ERα positive breast cancer.

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“…Zheng et al . proposed that FN causes epithelial cells to become refractory to tamoxifen by binding to β1 integrin ( 21 , 22 ). Consistent with these reports, we found that patients with luminal type A breast cancer with high levels of FN showed shorter relapse-free survival.…”

Section: Discussionmentioning

confidence: 99%

Fibronectin expression is upregulated by PI-3K/Akt activation in tamoxifen-resistant breast cancer cells

et al. 2017

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Fibronectin (FN) plays important roles in the EMT in a variety of cancer cell types. However, the mechanism by which FN expression is regulated in tamoxifen-resistant (TamR) breast cancer cells has not yet been fully elucidated. Aberrant FN expression was associated with poor prognosis in patients with luminal type A breast cancer. In addition, FN was upregulated in TamR cells. To investigate the mechanism by which FN expression is regulated, we assessed the levels of phosphorylated Akt, JNK, and STAT3 and found that they were all increased in TamR cells. Induction of FN expression was dampened by LY294002 or AKT IV in TamR cells. Furthermore, FN expression was increased by constitutively active (CA)-Akt overexpression in tamoxifen-sensitive MCF7 (TamS) cells and colony formation of TamR cells was blocked by AKT IV treatment. Taken together, these results demonstrate that FN expression is upregulated through the PI-3K/Akt pathway in tamoxifen-resistant breast cancer cells.

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Endocrine resistance in breast cancer

Cited by 12 publications

References 38 publications

Microenvironment-Induced Non-sporadic Expression of the AXL and cKIT Receptors Are Related to Epithelial Plasticity and Drug Resistance

Microenvironment-Induced Non-sporadic Expression of the AXL and cKIT Receptors Are Related to Epithelial Plasticity and Drug Resistance

DMXL2 drives epithelial to mesenchymal transition in hormonal therapy resistant breast cancer through notch hyper-activation

Fibronectin expression is upregulated by PI-3K/Akt activation in tamoxifen-resistant breast cancer cells

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