Journal Article

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

Granja-Ingram, Nara M, Meszoely, Ingrid M, Stemke-Hale, Katherine, Cook, Rebecca S, Dowsett, Mitch, Sanders, Melinda E, Pinto, Joseph A, Arteaga, Carlos L, Vaught, David B, Smith, J Joshua, Kuba, María G, Bhola, Neil E, González-Angulo, Ana M, Balko, Justin M, Mills, Gordon B, Gómez, Henry L, Miller, Todd W, Salter, Janine

2012

Overview

By digital profiling of residual breast tumors after neoadjuvant therapy, the authors identify gene expression patterns that correspond with a higher risk of metastasis and recurrence. Activation of the Ras-ERK pathway through loss of DUSP4 confers therapy resistance that can be overcome by combined treatment with MEK inhibitors. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 692/53 / 692/699/67/1059/2326 / 692/699/67/1347 / 692/700/565/1436/434 / Adjuvant treatment / Animals / Apoptosis / Biomedical and Life Sciences / Biomedicine / Breast cancer / Breast Neoplasms - classification / Breast Neoplasms - drug therapy / Breast Neoplasms - enzymology / Breast Neoplasms - genetics / Cancer / Cancer Research / Cell Survival / Chemotherapy / Drug resistance / Drug Resistance, Neoplasm - genetics / Drug therapy / Dual-Specificity Phosphatases - deficiency / Dual-Specificity Phosphatases - genetics / Dual-Specificity Phosphatases - metabolism / Enzyme Activation / Extracellular Signal-Regulated MAP Kinases - metabolism / Female / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Gene Knockdown Techniques / Genes, Neoplasm - genetics / Humans / Infectious Diseases / Ki-67 Antigen - metabolism / MAP Kinase Signaling System - genetics / Metabolic Diseases / Methylation / Mice / Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors / Mitogen-Activated Protein Kinase Kinases - metabolism / Mitogen-Activated Protein Kinase Phosphatases - deficiency / Mitogen-Activated Protein Kinase Phosphatases - genetics / Mitogen-Activated Protein Kinase Phosphatases - metabolism / Molecular Medicine / Neoadjuvant Therapy / Neoplasm, Residual / Neurosciences / Paraffin Embedding / ras Proteins - metabolism / RNA, Messenger - genetics / RNA, Messenger - metabolism / Tissue Banks / Tissue Fixation / Treatment Outcome / Tumors