Untitled

Le, Xiao Feng; Varela, Carmen; Bast, Robert C.

doi:10.1023/a:1020682807922

Cited by 22 publications

(7 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We observed that ERK/MAPK, STAT3 and CREB were inhibited in both sensitive and resistant breast cancer cell lines, whereas JNK and STAT5A/B were only inhibited in the sensitive cell line SKBR3, which suggests that in addition to hyperactivity of HER and of downstream PI3K signaling [ 24 ] these two parameters also contribute to the development of resistance of breast cancer cells against HER-TKIs. This hypothesis is supported by studies in pancreatic and prostate cancer, which also suggest a role for JNK activation in the development of resistance to HER targeting [ 16 , 17 , 29 – 31 ]. Moreover, EGF- and HRG-b1-induced phosphorylation of STAT5 has similarly been shown to modulate HER signaling and may thus also affect HER-TKI efficacy [ 32 – 36 ].…”

Section: Discussionmentioning

confidence: 77%

“…The HER family also controls tumor cell proliferation and apoptosis through separate, less known pathways. These pathways involve STAT5A/B, p38 and JNK, which regulate caspase activation and PARP-1 cleavage via BCL2 [ 16 , 17 ]. Surprisingly, the effect of pan-HER-targeted TKIs on these pathways has never been evaluated, even though modulation of proliferation and control of cell death are essential for the fate of a malignant breast tumor.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

HER Specific TKIs Exert Their Antineoplastic Effects on Breast Cancer Cell Lines through the Involvement of STAT5 and JNK

et al. 2016

View full text Add to dashboard Cite

BackgroundHER-targeted tyrosine kinase inhibitors (TKIs) have demonstrated pro-apoptotic and antiproliferative effects in vitro and in vivo. The exact pathways through which TKIs exert their antineoplastic effects are, however, still not completely understood.MethodsUsing Milliplex assays, we have investigated the effects of the three panHER-TKIs lapatinib, canertinib and afatinib on signal transduction cascade activation in SKBR3, T47D and Jurkat neoplastic cell lines. The growth-inhibitory effect of blockade of HER and of JNK and STAT5 signaling was measured by proliferation- and apoptosis-assays using formazan dye labeling of viable cells, Western blotting for cleaved PARP-1 and immunolabeling for active caspase 3, respectively.ResultsAll three HER-TKIs clearly inhibited proliferation and increased apoptosis in HER2 overexpressing SKBR3 cells, while their effect was less pronounced on HER2 moderately expressing T47D cells where they exerted only a weak antiproliferative and essentially no pro-apoptotic effect. Remarkably, phosphorylation/activation of JNK and STAT5A/B were inhibited by HER-TKIs only in the sensitive, but not in the resistant cells. In contrast, phosphorylation/activation of ERK/MAPK, STAT3, CREB, p70 S6 kinase, IkBa, and p38 were equally affected by HER-TKIs in both cell lines. Moreover, we demonstrated that direct pharmacological blockade of JNK and STAT5 abrogates cell growth in both HER-TKI-sensitive as well as -resistant breast cancer cells, respectively.ConclusionWe have shown that HER-TKIs exert a HER2 expression-dependent anti-cancer effect in breast cancer cell lines. This involves blockade of JNK and STAT5A/B signaling, which have been found to be required for in vitro growth of these cell lines.

show abstract

Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

HER Specific TKIs Exert Their Antineoplastic Effects on Breast Cancer Cell Lines through the Involvement of STAT5 and JNK

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Whereas HRG signaling exerts stimulatory effects on breast cancer cells (2,6,39), there are also contradictory results showing that activation of HRG signaling exerts inhibitory effects on breast cancer cell growth and survival (1,29,47). When, how, and in which conditions HRG functions as stimulatory or inhibitory molecules in breast cancer cells is not clearly understood (48).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Interactions between Heregulin and Peroxisome Proliferator-activated Receptor-γ (PPARγ) Agonist in Breast Cancer Cells

Park

Lee

Stolz³

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Here, we demonstrate that troglitazone (Rezulin), a peroxisome proliferator-activated receptor agonist, acted in synergy with heregulin to induce massive cell death in breast cancer cells. Although the combination of heregulin and troglitazone (HRG/TGZ) induced both apoptosis and necrosis, the main mode of cell death was caspase-independent and occurred via necrosis. This combination increased generation of superoxide in mitochondria, which in turn destabilized mitochondria potential. Pretreatment with N-acetyl-L-cysteine and catalase expression ameliorated cell death induced by the combination treatment, indicating a role of oxidative stress in mediating HRG/TGZ-induced cell death. Notably, pretreatment with pyruvate significantly prevented the cell death, suggesting a potential mechanistic link between metabolic stress and HRG/ TGZ-induced cell death. The activation of the HRG signaling axis has been considered as a poor prognostic factor in breast cancer and confers resistance to gefitinib (Iressa) and tamoxifen. However, our data presented here paradoxically suggest that HRG expression can actually be beneficial when it comes to treating breast cancer with peroxisome proliferator-activated receptor-␥ ligands. Taken together, the combination of HRG and TGZ may provide a basis for the development of a novel strategy in the treatment of apoptosis-resistant and/or hormone-refractory breast cancer.Breast cancer is the second most common cause of cancer death, accounting for one in three of all cancer cases diagnosed in women. Although overall survival continues to improve for breast cancer, intrinsic or acquired therapy resistance has been an ongoing obstacle to reducing overall breast cancer mortality. Combining different drugs is now widely used to overcome the problem of therapy resistance. Combination therapy often increases the likelihood of response, and in ideal combination may even be synergistic rather than simply additive. In addition, by keeping each drug at low dose, there can be the potential advantages of longer duration of action and less side effects.Heregulin (HRG), 2 also known as neuregulin or neu differentiation factor, is a soluble secreted growth factor. The HRG gene family consists of four members, HRG-1, HRG-2, HRG-3, and HRG-4, of which a multitude of different isoforms are synthesized by alternative exon splicing (1). HRG binds to HER3 receptors or HER4 receptors, or both, resulting in the formation of receptor homo-and heterodimerization. In mammary epithelial cells, HRG predominantly uses HER2 and HER3 dimers. Upon engagement of HRG with the heregulin extracellular domain, multiple signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)/AKT, RAS/MAPK, and JNK pathways, are activated. To date, most studies have shown that HRG exhibits a growth-stimulatory effect in a variety of cancer cells, including breast cancer cells. Several lines of evidence implicated activation of human epidermal growth factor receptors by HRG as a primary driver of malignancy (2-4). Activation of H...

show abstract

“…TRAIL, a member of the TNF family, induces apoptosis by binding receptors and recruiting the Fas-associated death domain and caspase-8, triggering apoptosis [100]. Heregulin is a soluble secreted growth factor that activates several classic tumourigenic signal transduction pathways including PI3K/Akt, Ras/MAPK, and JNK [101]. …”

Section: Cell Signaling Moleculesmentioning

confidence: 99%

The Key to Unlocking the Chemotherapeutic Potential of PPARγLigands: Having the Right Combination

Skelhorne‐Gross

Nicol

2012

PPAR Research

View full text Add to dashboard Cite

Despite extensive preclinical evidence that peroxisome proliferator-activated receptor (PPAR)γ activation protects against tumourigenesis, results from a few clinical trials using PPARγ ligands as monotherapy show modest success. In spite of this, several groups reported exciting results with therapeutic regimens that combine PPARγ ligands with other compounds: chemotherapeutic agents, retinoid x receptor (RXR)α agonists, statins, or cell-to-cell signaling molecules in preclinical cancer models and human trials. Here we have compiled an extensive review, consolidating the existing literature, which overwhelmingly supports a beneficial effect of treating with PPARγ ligands in combination with existing chemotherapies versus their monotherapy in cancer. There are many examples in which combination therapy resulted in synergistic/additive effects on apoptosis, differentiation, and the ability to reduce cell growth and tumour burden. There are also studies that indicate that PPARγ ligand pretreatment overcomes resistance and reduces toxicities. Several mechanisms are explored to explain these protective effects. This paper highlights each of these studies that, collectively, make a very strong case for the use of PPARγ ligands in combination with other agents in the treatment and management of several cancers.

show abstract

Untitled

Cited by 22 publications

References 51 publications

HER Specific TKIs Exert Their Antineoplastic Effects on Breast Cancer Cell Lines through the Involvement of STAT5 and JNK

HER Specific TKIs Exert Their Antineoplastic Effects on Breast Cancer Cell Lines through the Involvement of STAT5 and JNK

Synergistic Interactions between Heregulin and Peroxisome Proliferator-activated Receptor-γ (PPARγ) Agonist in Breast Cancer Cells

The Key to Unlocking the Chemotherapeutic Potential of PPARγLigands: Having the Right Combination

Contact Info

Product

Resources

About