In melanoma metastasis, the role of the AP-2α transcription factor, which is encoded by TFAP2A, is controversial as some findings have suggested tumor suppressor activity while other studies have shown high TFAP2A expression in node-positive melanoma associated with poor prognosis. Here we demonstrate that AP-2α facilitates melanoma metastasis through transcriptional activation of genes within the E2F pathway including EZH2. A BioID screen found that AP-2α interacts with members of the nucleosome remodeling and deacetylase (NuRD) complex. Loss of AP-2α removed activating chromatin marks in the promoters of EZH2 and other E2F target genes through activation of the NuRD repression complex. In melanoma cells, treatment with tazemetostat, an FDA-approved and highly specific EZH2 inhibitor, substantially reduced anchorage-independent colony formation and demonstrated heritable antimetastatic effects, which were dependent on AP-2α. Single-cell RNA sequencing analysis of a metastatic melanoma mouse model revealed hyperexpansion of Tfap2aHigh/E2F-activated cell populations in transformed melanoma relative to progenitor melanocyte stem cells. These findings demonstrate that melanoma metastasis is driven by the AP-2α/EZH2 pathway and suggest that AP-2α expression can be used as a biomarker to predict responsiveness to EZH2 inhibitors for the treatment of advanced melanomas. Significance: AP-2α drives melanoma metastasis by upregulating E2F pathway genes including EZH2 through inhibition of the NuRD repression complex, serving as a biomarker to predict responsiveness to EZH2 inhibitors.

◥The AP-2g transcription factor, encoded by the TFAP2C gene, regulates the expression of estrogen receptor-alpha (ERa) and other genes associated with hormone response in luminal breast cancer. Little is known about the role of AP-2g in other breast cancer subtypes. A subset of HER2 þ breast cancers with amplification of the TFAP2C gene locus becomes addicted to AP-2g. Herein, we sought to define AP-2g gene targets in HER2 þ breast cancer and identify genes accounting for physiologic effects of growth and invasiveness regulated by AP-2g. Comparing HER2 þ cell lines that demonstrated differential response to growth and invasiveness with knockdown of TFAP2C, we identified a set of 68 differentially expressed target genes. CDH5 and CDKN1A were among the genes differentially regulated by AP-2g and that contributed to growth and invasiveness. Pathway analysis implicated the MAPK13/p38d and retinoic acid regulatory nodes, which were confirmed to display divergent responses in different HER2 þ cancer lines. To confirm the clinical relevance of the genes identified, the AP-2g gene signature was found to be highly predictive of outcome in patients with HER2 þ breast cancer. We conclude that AP-2g regulates a set of genes in HER2 þ breast cancer that drive cancer growth and invasiveness. The AP-2g gene signature predicts outcome of patients with HER2 þ breast cancer and pathway analysis predicts that subsets of patients will respond to drugs that target the MAPK or retinoic acid pathways.Implications: A set of genes regulated by AP-2g in HER2 þ breast cancer that drive proliferation and invasion were identified and provided a gene signature that is predictive of outcome in HER2 þ breast cancer. Materials and Methods Cell cultureCell lines HCC1954, SKBR3, MCF-7, HCC202, HCC1569, and MDA-MB-453 were purchased from the ATCC, used at low (<10) passage number without further authentication or Mycoplasma testing, and propagated in the appropriate medium as recommended by the manufacturer. For experiments with all-trans-retinoic acid

For women from rural communities, IORT appears to be an attractive option because these women tend to be older and to live farther from the treatment facility.

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