Pathways Up-Regulated in Basal-Like Breast Cancer.
Minghao Zhong, Lin Gao, Xin Zhao, Matthew Geller, Fei Ye, David Zhang, Dong Song. The Mount Sinai Medical Center, New York, NY; The First Hospital, Jilin University, Changchun, China
Background: Breast cancer is the most common malignancy in women and is second only to lung carcinoma in cancer mortality. Molecular classification of breast cancer in the last decade has generated a new era of personalized medicine for this heterogeneous disease. Basal-like breast cancer (BLBC) is a particularly aggressive subtype defined by a robust cluster of genes expressed in the basal (outer) layer of the adult mammary gland. BLBC is a major clinical challenge because these tumors are prevalent in young women and often have a rapidly relapsing course. Additionally, most BLBC lack expression of steroid hormone receptors and human epidermal growth factor receptor 2 (HER2), limiting targeted therapeutic options for these predominantly triple-negative breast cancers. The aim of this study is to identify activated protein pathways in BLBC
Design: Protein Pathway Array was used to assess the level of protein expression and phosphorylation in several breast cancer cell lines (MDA-MB-231 [Basal like]; MCF-7 [Luminal A]; T47D [Luminal B]) and a normal breast cell line (MCF10A). A total of 159 antibodies representing the most important signal transduction pathways involved in proliferation, apoptosis, angiogenesis, invasion and metastasis were evaluated. Several potential therapeutic kinase proteins were also assessed.
Results: A total 42 proteins (including phospho-PDK1, p-CDC2, cyclin E1, cPKC alpha, HSP90, PCNA, AKT, CDC2, PTEN, NFkB, CDC42 and FAS) were differentially expressed between normal (MCF10A) and cancer cell lines. Compared MDA-MB-231 with other cancer cells, 10 proteins were differentially expressed in MDA-MB-231. Among these proteins, 7 were up-regulated (p-P53, p-RB, p38, ERK, CDK6, NOTCH and CDC42) and 3 was down-regulated (p-PKC delta, E-cadherin and TNF-alpha). The expression levels of these proteins were further confirmed in 37 breast cancer tissues using Protein Pathway Array.
Conclusions: Our study shows that distinct sets of signaling pathways are activated in BLBC. The growth factor pathway (p38/ERK), Notch pathway, p53 pathway and RB pathway were predominantly up-regulated or activated in BLBC. In contrast, the PKC, E-cadherin and TNF pathways were down-regulated. Furthermore, different set of cell cycle progression proteins (CDK46 and CDC42) were upregulated in BLBC. Our data suggest that several pathways other than HER2 and ER pathways were activated in BLBC which may explain its distinct clinical behaviors. These findings may be used to design future clinical trials of BLBC based on the activation of various signaling pathways.
Monday, February 28, 2011 1:00 PM
Poster Session II # 62, Monday Afternoon