Proteomic Signatures of Acquired Letrozole Resistance in Breast Cancer: Suppressed Estrogen Signaling and Increased Cell Motility and Invasiveness

Tilghman, Syreeta L.; Townley, Ian K.; Zhong, Qi; Carriere, Patrick P.; Zhang, Jin; Llopis, Shawn D.; Preyan, Lynez C.; Williams, Christopher C.; Skripnikova, Elena; Bratton, Melyssa R.; Zhang, Qiang; Wang, Guangdi

doi:10.1074/mcp.m112.023861

Cited by 51 publications

(52 citation statements)

References 89 publications

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“…Gene expression profiling of tumor biopsies from a proportion of patients included in this study has previously revealed that substantially more genes were changed at three months than at two weeks on AI treatment [42]. Thus, the changes in EGFR/HER-1 and in particular NRG1 could be related to tumor heterogeneity and clonal selection potentially related to primary effects of deregulated ERsignaling in the tumors [9,43,44].…”

Section: Treatment With Ais For 3-4 Months Suppresses Total Body Estrmentioning

confidence: 77%

“…EGFR/HER-1, HER-2/neu and Insulin-like Growth Factor 1 Receptor (IGF-IR) [8][9][10][11]. This has also been confirmed in xenograft models where adaption of the cells to low estrogen levels is accompanied by up-regulation of HER-2/neu and downregulation of ER and aromatase activity [12,13].…”

Section: Introductionmentioning

confidence: 78%

“…The increase in EGFR/HER-1 and NRG1 during estrogen deprivation reported in the present clinical study supports the role of an intimate cross-talk between ER and growth factor receptor signaling pathways during endocrine treatment [18,46] . Using different in vitro models mimicking AI resistance, increased expression of HER-receptors, and in particular EGFR/HER-1, accompanied by diminished ER-regulated signaling has been demonstrated [8,9,11]. However, the knowledge of EGFR/HER-1 and NRG1 expression and activity in breast tumors during AI therapy and development of resistance is limited.…”

Section: Treatment With Ais For 3-4 Months Suppresses Total Body Estrmentioning

confidence: 99%

“…In vitro and in vivo xenograft studies analyzing adaptive signaling events in the development of resistance have revealed that the cellular changes are complex and may vary in-between model systems [9,20,79,80]. Analyses of global gene expression have also…”

Section: Treatment With Ais For 3-4 Months Suppresses Total Body Estrmentioning

confidence: 99%

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Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers

Flågeng

Larionov

Geisler

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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While estrogens have been shown to modulate EGFR/HER-1 and HER-2/neu expression in experimental systems, the effects of estrogen deprivation on expression levels of the HER-receptors and the neuregulin (NRG)1 ligand in breast cancers remain unknown. Here, we measured EGFR/HER-1-4 and NRG1 mRNA in ER positive tumors from 85 postmenopausal breast cancer patients before and after two weeks (n=64) and three months (n=85) of primary treatment with an aromatase inhibitor (AI). In tumors lacking HER-2/neu amplification, quantitative real-time PCR analyses revealed EGFR/HER-1 and NRG1 to vary significantly between the three time points (before therapy, after 2 weeks and after 3 months on treatment; P≤0.001 for both). Pair-wise comparison revealed a significant increase in EGFR/HER-1 already during the first two weeks of treatment (P=0.049) with a further increase for both EGFR/HER-1 and NRG1 after 3 months on treatment (P≤0.001 and P=0.001 for both comparing values at 3 months to values at baseline and 2 weeks respectively). No difference between tumors responding versus non-responders was recorded. Further, no significant change in any parameter was observed among HER-2/neu amplified tumors. Analyzing components of the HER-2/neu PI3K/Akt downstream pathway, the PIK3CA H1047R mutation was associated with treatment response (P=0.035); however no association between either AKT phosphorylation status or PIK3CA gene mutations and EGFR/HER-1 or NRG1 expression levels were observed. Our results indicate primary AI treatment to modulate expression of HER-family members and the growth factor NRG1 in HER-2/neu non-amplified breast cancers in vivo. Potential implications to long term sensitivity warrants further investigations.

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Section: Treatment With Ais For 3-4 Months Suppresses Total Body Estrmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 78%

Section: Treatment With Ais For 3-4 Months Suppresses Total Body Estrmentioning

confidence: 99%

Section: Treatment With Ais For 3-4 Months Suppresses Total Body Estrmentioning

confidence: 99%

See 2 more Smart Citations

Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers

Flågeng

Larionov

Geisler

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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“…However, the field is wider and is still expanding with the exploitation of new and alternative approaches, e.g. dynamic PET imaging [147], proteomic signatures [148], genetic polymorphisms [149][150][151][152][153][154] and epigenetic changes (see Luca Magnani's chapter in this book). Reviewing of all the emerging directions would be beyond the scope of this review.…”

Section: Emerging Technologies and Markersmentioning

confidence: 99%

Prediction of Response to Aromatase Inhibitors in Breast Cancer

Larionov

Miller

2015

Resistance to Targeted Anti-Cancer Therapeutics

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Aromatase inhibitors (AIs) are major treatment options for the management of patients with breast cancer. The drugs are effective and response rates can be high. However, resistance, either primary or acquired during treatment, may occur. Optimal clinical management requires accurate predictors of response to identify those tumours, which are most likely to respond (so sparing patients with resistant tumours needless side-effects of ineffective therapy). Currently, oestrogen receptor (ER) status is the only factor used routinely to select for treatment with aromatase inhibitors, but a substantial proportion of ER-positive tumours fails treatment. There is, therefore, an urgent need to identify additional markers by which accurately to predict clinical response on an individual basis. Whilst other markers (such as progesterone receptors or HER2) have some predictive powers, individually they have limited utility for routine use. The hope is that discovery strategies based on genome-wide searches will identify novel markers that can be used as predictive indices. Molecular phenotyping of individual tumours could then be used to decide not only which patients should be treated with AIs but whether AIs should be used alone or in combination or in sequence with other targeted agents in order that clinical benefits are maximized. This chapter will focus on utility of routinely assessed biomarkers, multi-component indices and gene signatures and outline the future perspectives in studies aimed to AI response prediction.

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The TGFβ2‐Snail1‐miRNA_TGFβ2 Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer

Luo,

Xu,

Fan

et al. 2024

Clinical & Translational Med

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There have been contradictory reports on the biological role of transforming growth factor‐βs (TGFβs) in breast cancer (BC), especially with regard to their ability to promote epithelial‐mesenchymal transition (EMT). Here, we show that TGFβ2 is preferentially expressed in mesenchymal‐like BCs and maintains the EMT phenotype, correlating with cancer stem cell‐like characteristics, growth, metastasis and chemo‐resistance and predicting worse clinical outcomes. However, this is only true in ERα− BC. In ERα+ luminal‐type BC, estrogen receptor interacts with p‐Smads to block TGFβ signalling. Furthermore, we also identify a microRNAs (miRNAs) signature (miRNAsTGFβ2) that is weakened in TGFβ2‐overexpressing BC cells. We discover that TGFβ2‐Snail1 recruits enhancer of zeste homolog‐2 to convert miRNAsTGFβ2 promoters from an active to repressive chromatin configuration and then repress miRNAsTGFβ2 transcription, forming a negative feedback loop. On the other hand, miRNAsTGFβ2 overexpression reverses the mesenchymal‐like traits in agreement with the inhibition of TGFβ2‐Snail1 signalling in BC cells. These findings clarify the roles of TGFβ2 in BC and suggest novel therapeutic strategies based on the TGFβ2‐Snail1‐miRNAsTGFβ2 loop for a subset type of human BCs.

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Proteomic Signatures of Acquired Letrozole Resistance in Breast Cancer: Suppressed Estrogen Signaling and Increased Cell Motility and Invasiveness

Cited by 51 publications

References 89 publications

Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers

Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers

Prediction of Response to Aromatase Inhibitors in Breast Cancer

The TGFβ2‐Snail1‐miRNA_TGFβ2 Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer

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Proteomic Signatures of Acquired Letrozole Resistance in Breast Cancer: Suppressed Estrogen Signaling and Increased Cell Motility and Invasiveness

Cited by 51 publications

References 89 publications

Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers

Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers

Prediction of Response to Aromatase Inhibitors in Breast Cancer

The TGFβ2‐Snail1‐miRNATGFβ2 Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer

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The TGFβ2‐Snail1‐miRNA_TGFβ2 Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer