Nodal signaling promotes a tumorigenic phenotype in human breast cancer

Kirsammer, Gina; Strizzi, Luigi; Margaryan, Naira V.; Gilgur, Alina; Hyser, Matthew; Atkinson, Janis; Kirschmann, Dawn A.; Seftor, Elisabeth A.; Hendrix, Mary J.C.

doi:10.1016/j.semcancer.2014.07.007

Cited by 41 publications

(59 citation statements)

References 27 publications

(34 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These data advance a previous study in which Nodal expression was found to be significantly higher in TNBC compared to benign breast tissue. 17 These results also support the prospect that Nodal represents a targetable molecule for TNBC and other receptor-negative breast cancers in which current targeted therapies are not effective. In line with this observation, a previous study identified Nodal as a prognostic marker for aggressive breast cancer independent of HR status or HER2 expression.…”

Section: Discussionsupporting

confidence: 55%

“…17 To advance these initial observations, we compared Nodal expression in TNBC to other invasive breast cancer subtypes using an additional 32 TNBC samples and 49 invasive breast cancer samples of differing HR and HER2 status. Scoring immunohistochemistry (IHC) samples for Nodal revealed significantly higher levels in TNBC compared to any HR/HER2 positive cases (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…For example, recent findings that have reported the embryonic morphogen Nodal as a driver of cancer cell growth, plasticity, and highly expressed in aggressive cancers, are complemented by experimental studies showing Nodal inhibition resulting in suppression of tumorigenesis and the cancer stem cell phenotype. 13,17,31 In this study, we analyzed Nodal expression in a group of invasive breast cancer samples and found Nodal to be more highly expressed in TNBC when compared to invasive HR and HER2 positive breast cancers. These data advance a previous study in which Nodal expression was found to be significantly higher in TNBC compared to benign breast tissue.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Nodal expression in triple-negative breast cancer: Cellular effects of its inhibition following doxorubicin treatment

et al. 2016

Self Cite

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC) represents an aggressive cancer subtype characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The independence of TNBC from these growth promoting factors eliminates the efficacy of therapies which specifically target them, and limits TNBC patients to traditional systemic neo/ adjuvant chemotherapy. To better understand the growth advantage of TNBC -in the absence of ER, PR and HER2, we focused on the embryonic morphogen Nodal (associated with the cancer stem cell phenotype), which is re-expressed in aggressive breast cancers. Most notably, our previous data demonstrated that inhibition of Nodal signaling in breast cancer cells reduces their tumorigenic capacity. Furthermore, inhibiting Nodal in other cancers has resulted in improved effects of chemotherapy, although the mechanisms for this remain unknown. Thus, we hypothesized that targeting Nodal in TNBC cells in combination with conventional chemotherapy may improve efficacy and represent a potential new strategy. Our preliminary data demonstrate that Nodal is highly expressed in TNBC when compared to invasive hormone receptor positive samples. Treatment of Nodal expressing TNBC cell lines with a neutralizing anti-Nodal antibody reduces the viability of cells that had previously survived treatment with the anthracycline doxorubicin. We show that inhibiting Nodal may alter response mechanisms employed by cancer cells undergoing DNA damage. These data suggest that development of therapies which target Nodal in TNBC may lead to additional treatment options in conjunction with chemotherapy regimens -by altering signaling pathways critical to cellular survival.

show abstract

Section: Discussionsupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Nodal expression in triple-negative breast cancer: Cellular effects of its inhibition following doxorubicin treatment

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…These results are consistent with other reports, which suggest that E2 bound ERa induced cell proliferation via activation of ERK and Akt. [12][13][14]32 Cisplatin induces activation of the ERK and Akt cascades, which promote cell survival and correlate with platinum resistance. 33 However, it was not previously known that cisplatin activates ERa in ovarian cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies show that E2-stimulated ERa promotes cell proliferation via activation of the extracellular signal regulated protein kinases (ERK) in breast cancer cells. 13,14 We previously reported that the phosphatidylinositol 3-kinase (PI3K)-Akt cascade is activated by E2 bound ERa in ovarian cancer cells. 15 The Ras/Raf/ERK and PI3K/Akt pathways are involved in proliferation, invasion, metastasis and survival in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Activation of estrogen receptor α by estradiol and cisplatin induces platinum-resistance in ovarian cancer cells

Matsumura

Ohta

Yamanouchi

et al. 2016

Cancer Biology & Therapy

View full text Add to dashboard Cite

Activation of Estrogen receptor (ER) a (a) promotes cell growth and influences the response of cancer cell to chemotherapeutic agents. However, the mechanism by which ERa activation antagonizes cells to chemotherapy-induced cytotoxicity remains unclear. Here, we investigated the effect of cisplatin on ERa activation. In addition, we examined whether down-regulation of ERa modulate cisplatin-mediated cytotoxicity using 2 human ovarian cancer cells (Caov-3 and Ovcar-3) transduced with ERa short hairpin RNA (shRNA). The proliferation assay showed that 17b-estradiol (E2) induced cell proliferation via activation of Akt and extracellular signal-regulated kinase (ERK) cascades, while shRNA mediated downregulation of ERa inhibited the cell proliferation. Immunoblot analysis revealed that cisplatin induced the phosphorylation of ERa at serine 118 via ERK cascade. Luciferase assay showed that cisplatin increases transcriptional activity of estrogen-responsive element (ERE). The E2-stimulated ERa activation attenuated cisplatin-induced cytotoxicity. Meanwhile, down-regulation of ERa inhibited E2-induced protective effect on cisplatin toxicity as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Moreover, Pretreatment with E2 followed by cisplatin decreased the expression of cleaved PARP, and increased the expression of anti-apoptotic protein Bcl-2. Collectively, our findings suggest that activation of ERa by E2 and cisplatin can induce platinum-resistance by increasing the expression of antiapoptotic protein in ovarian cancer cells. Therefore, our findings provide valuable information that ERa might be a promising therapeutic target for platinum-resistant ovarian cancer.Abbreviations: ER, estrogen receptor; ERK, extracellular signal regulated protein kinase; PI3K, phosphatidylinositol 3-kinase.

show abstract

Nodal increases the malignancy of childhood neuroblastoma cells via regulation of Zeb1

Cheng

Huang

et al. 2019

BioFactors

View full text Add to dashboard Cite

Neuroblastoma (NB) is one of the most common malignant tumors derived from pluripotent cells of the neural crest. Nodal is an important embryonic morphogen which can re-express in cancer cells. The roles of Nodal in the progression of NB are not illustrated. Our present study reveals that Nodal is upregulated in NB cells and tissues. Targeted inhibition of Nodal can suppress the in vitro migration and invasion of NB cells while increase its chemo-sensitivity to doxorubicin (Dox) treatment. Nodal positively regulates the expression of Zeb1, one well-known transcription factors of epithelial to mesenchymal transition (EMT) of cancer cells. Knockdown of Zeb1 can attenuate Nodal-induced malignancy of NB cells. Mechanistically, Nodal increases the protein stability of Zeb1 while has no effect on its mRNA expression. It is due to that Nodal can increase the expression of Ataxia telangiectasia mutated kinase (ATM), which can phosphorylate and stabilize Zeb1 in cancer cells. Collectively, our data revealed that Nodal can increase the malignancy of NB cells via increasing the expression of Zeb1. It suggests that targeted inhibition of Nodal might be a potential therapy approach for NB treatment. © 2019 BioFactors, 45(3): [355][356][357][358][359][360][361][362][363] 2019

show abstract

Nodal signaling promotes a tumorigenic phenotype in human breast cancer

Cited by 41 publications

References 27 publications

Nodal expression in triple-negative breast cancer: Cellular effects of its inhibition following doxorubicin treatment

Nodal expression in triple-negative breast cancer: Cellular effects of its inhibition following doxorubicin treatment

Activation of estrogen receptor α by estradiol and cisplatin induces platinum-resistance in ovarian cancer cells

Nodal increases the malignancy of childhood neuroblastoma cells via regulation of Zeb1

Contact Info

Product

Resources

About