c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer

Abstract

The HER2 (ERBB2) and MYC genes are commonly amplified in breast cancer, yet little is known about their molecular and clinical interaction. Using a novel chimeric mammary transgenic approach and in vitro models, we demonstrate markedly increased self-renewal and tumour-propagating capability of cells transformed with Her2 and c-Myc. Coexpression of both oncoproteins in cultured cells led to the activation of a c-Myc transcriptional signature and acquisition of a self-renewing phenotype independent of an epithelial-mesenchymal transition programme or regulation of conventional cancer stem cell markers. Instead, Her2 and c-Myc cooperated to induce the expression of lipoprotein lipase, which was required for proliferation and self-renewal in vitro. HER2 and MYC were frequently coamplified in breast cancer, associated with aggressive clinical behaviour and poor outcome. Lastly, we show that in HER2(+) breast cancer patients receiving adjuvant chemotherapy (but not targeted anti-Her2 therapy), MYC amplification is associated with a poor outcome. These findings demonstrate the importance of molecular and cellular context in oncogenic transformation and acquisition of a malignant stem-like phenotype and have diagnostic and therapeutic consequences for the clinical management of HER2(+) breast cancer.

Semi-comprehensive analysis of gene amplification in gastric cancers using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization

“…Instead, new data have shown that this coamplification is associated with poor outcome and is associated with the sequence of acquisition of a malignant stem cell-like phenotype that maintains lower growth and therefore may be a key target of new therapy. 28 TOP2A resides very close to ERBB2 on the chromosome and its amplification was only observed with the concomitant amplification of ERBB2. However, TOP2A is not simply a 'passenger' gene because TOP2A encodes an enzyme, topoisomerase IIα, which is required for DNA replication.…”

Downregulation of c-Myc is involved in TLR3-mediated tumor death of neuroblastoma xenografts

“…39 Positive TLR3 expression was considered a favorable prognostic factor whereas positive c-Myc protein expression is a poor prognostic factor by clinical research of NB. 8,20 However, elevated TLR3 expression in breast cancer and overexpression of c-Myc in HER2-positive breast cancer were respectively determined as a poor prognostic factor, 40,41 and TLR3 treatment was associated with overexpression of c-Myc to facilitate stem cells potential. 40 In addition, overexpression of TLR3 and c-Myc was reported to be induced by poly(I:C) treatment, which led to cell proliferation in head and neck cancer.…”

K9(C4H4FN2O2)2Nd(PW11O39)2·25H2O induces apoptosis in human lung cancer A549 cells

“…Combination treatment with triptolide and hydroxycamptothecin synergistically enhances apoptosis by increasing the ratio of Bax/Bcl-2 in A549 cells (24). Formononetin-induced apoptosis was accompanied by upregulation of Bax and downregulation of Bcl-2, with the consequent dysfunction of mitochondria and activation of caspase-3 in A549 cells (25). Cactus pear extracts increased caspase3 and Bax protein levels, and decreased the Bcl-2 protein level in the lung cancer cell line A549 (26).…”