Rebecca Cook
Faculty Member
Last active: 4/15/2019

Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance.

Balko JM, Cook RS, Vaught DB, Kuba MG, Miller TW, Bhola NE, Sanders ME, Granja-Ingram NM, Smith JJ, Meszoely IM, Salter J, Dowsett M, Stemke-Hale K, González-Angulo AM, Mills GB, Pinto JA, Gómez HL, Arteaga CL
Nat Med. 2012 18 (7): 1052-9

PMID: 22683778 · PMCID: PMC3693569 · DOI:10.1038/nm.2795

Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ~30% of patients with breast cancer. However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR. We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance. Digital transcript counting was used to profile surgically resected breast cancers after NAC. Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status. BLBC had higher DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation relative to other breast cancer subtypes. DUSP4 overexpression increased chemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy. Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory high Ki-67 scores and shorter recurrence-free survival. Finally, inhibition of mitogen-activated protein kinase kinase (MEK) synergized with docetaxel treatment in BLBC xenografts. Thus, DUSP4 downregulation activates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancer chemotherapy.

MeSH Terms (27)

Animals Apoptosis Breast Neoplasms Cell Survival Drug Resistance, Neoplasm Dual-Specificity Phosphatases Enzyme Activation Extracellular Signal-Regulated MAP Kinases Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Knockdown Techniques Genes, Neoplasm Humans Ki-67 Antigen MAP Kinase Signaling System Mice Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinase Phosphatases Neoadjuvant Therapy Neoplasm, Residual Paraffin Embedding ras Proteins RNA, Messenger Tissue Banks Tissue Fixation Treatment Outcome

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