PD08-03: Inhibition of MEK/ERK- and JNK-Dependent Expression of Interleukin-6 and Interleukin-8 Targets Basal-Like Breast Cancer Stem Cells

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 24_Supplement; p. PD08-03
• Main Authors: Balko, JM, Cook, RS, Kuba, MG, Miller, TW, Bhola, NE, Sanders, ME, Meszoely, IM, Dowsett, M, Gomez, H, Arteaga, CL
• Format: Journal Article
• Language: English
• Published: 15.12.2011
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.SABCS11-PD08-03

Abstract Background: Neoadjuvant chemotherapy (NAC) induces a pathological complete response in approximately 30% of triple-negative or basal-like breast cancers (BLBC). However, patients with residual disease often recur after surgery, presumably due to persistent drug-resistant subpopulations with cancer stem cell (CSC)-like properties. Thus, elimination of this CSC compartment in BLBC has the potential to improve survival by reducing post-surgical metastatic recurrences. Methods: We sampled 49 post-NAC breast cancer samples including 22 BLBCs and quantified RNA for 355 cancer-related transcripts using Nanostring technology. Transcripts associated with a high Ki67 in the residual disease (a biomarker of early recurrence) were identified and bioinformatically examined for an association with drug resistance and a CSC phenotype. Loss of DUSP4, a negative feedback regulator of ERK1/2 and JNK1/2, was highly associated with a high post-NAC Ki67. We examined the role of loss of DUSP4 in promoting a drug-resistant, CSC phenotype. Results: Low DUSP4 expression in post-NAC tumors was associated with high ERK1/2 activation and BLBC gene expression. siRNA knockdown of DUSP4 enhanced resistance to anti-cancer chemotherapy (docetaxel, camptothecin). Alternatively, forced DUSP4 expression in breast cancer cell lines abrogated the activation of transcription factors downstream of ERK and JNK and sensitized cells to docetaxel-induced apoptosis. In highly metastastic BLBC cell lines, MEK inhibition with AZD6244 and JNK inhibition with SP600125 significantly reduced mammosphere formation and self-renewal. Inhibition of JNK and MEK reduced IL6 and IL8 expression, two cytokines known to expand the CSC compartment. Reconstitution of exogenous IL6 and IL8 after MEK inhibition restored mammosphere formation potential. Chromatin immunoprecipitation demonstrated that the oncogenic transcription factor ETS-1, an ERK1/2 substrate, binds the IL8 promoter in a MEK1/2-dependent manner. We are currently confirming the association of DUSP4 loss with Ki67, ERK activation, and IL6/IL8 expression in a cohort of 113 post-NAC triple negative breast cancers. Conclusions: Our data demonstrate that loss of DUSP4 in BLBC promotes ERK and JNK activation by impairing negative feedback of these pathways. Activation of ERK and JNK drives expression of IL6 and IL8 expression, possibly through ETS-1 activation. Thus, targeting these signaling pathways may eliminate residual cancer stem cells after neoadjuvant chemotherapy and improve cure rates in BLBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD08-03.