Abstract P2-08-05: FOXK2 aberration in breast cancer
Authors: Zhang H , Yu Y 
Published: February 2018

Background: Activation of oncogenes through DNA amplification/overexpression plays important roles in cancer initiation and progression. The chromosome 17 is a frequent site of cancer-associated genetic anomalies. This cytogenetic anomaly is strongly associated with poor prognosis and is a significant predictor of relapse in breast cancer. Previous studies of breast cancer have revealed the amplification of several genomic regions on 17q. These amplifications are typically discontinuous and complex in structure, suggesting that multiple oncogenes in this chromosomal segment may be co-selected during breast carcinogenesis. By integrative analysis of public genomic datasets of breast cancers from The Cancer Genome Atlas (TCGA), we have found that FOXK2 displayed frequent genomic amplifications and correlated gene expression changes in breast cancer. FOXK2 gene is located in 17q25 and encodes a transcriptional factor with a fork head DNA binding domain, but has not yet been reported to be associated with cancer-causal genetic aberrations. Gene amplification in the 17q chromosomal region is observed frequently in breast cancers. We hypothesize that FOXK2 is an important oncogene in breast cancer and it might be a novel therapeutic target and biomarker for breast cancer.

Methods: The status of FOXK2 located at the Chromosome 17q25 was explored by mining the breast cancer TCGA datasets including 910 tumor cases and 981 normal controls. To determine whether FOXK2 amplification/overexpression is required for breast cancer cell proliferation, we assessed the effect of FOXK2 stable knockdown on proliferation and anchorage-independent growth in four cell lines with high FOXK2 expression status (MDA-MB-231, MCF-7, HCC1954 and MDA-MB-361) using lentivirus mediated shRNAs. The oncogenic activity of FOXK2 was assessed by colony formation assay.The potential interacting molecules/pathways were explored

Results: Frequent genomic amplifications of FOXK2 were detected in breast cancers compared to normal controls in all subtypes of breast cancers classified by PAM50 by integrative analysis of public genomic datasets and its overexpression was associated with poor overall survival of breast cancer patients. FOXK2 knockdown in several breast cancer cell lines inhibited breast cancer cell proliferation and anchorage-independent growth. More importantly, overexpression of FOXK2 and oncogene RAS induced MCF10A cell colony formation, indicating that FOXK2 is an oncogene in breast cancer. Several pathways, including regulation of cell proliferation, regulation of cell division, cell adhesion and regulation of cell metabolism, were regulated by FOXK2 in breast cancer cells.

Conclusion: Our data provide compelling evidence that FOXK2 is an oncogene in breast tumorigenesis, and it might be a novel therapeutic target and a biomarker predicting poor outcome. We are assessing the incidence of FOXK2 amplification in human breast cancer specimens using immunohistochemistry and FISH on TMA tissue blocks to determine the prognostic value of FOXK2 amplification for overall prognosis and treatment resistance. We are also validating the molecular mechanism of FOXK2 in breast cancer malignancy according to the identified potential interacting molecules/pathways by analyzing the RNASeq data of a breast cancer cell line with FOXK2 knockdown.

Citation Format: Zhang H, Yu Y. FOXK2 aberration in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-08-05.