AP-2α-Mediated Activation of E2F and EZH2 Drives Melanoma Metastasis.

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 Tfap2a High/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.

A TFAP2C Gene Signature Is Predictive of Outcome in HER2-Positive Breast Cancer.

The AP-2γ transcription factor, encoded by the TFAP2C gene, regulates the expression of estrogen receptor-alpha (ERα) and other genes associated with hormone response in luminal breast cancer. Little is known about the role of AP-2γ in other breast cancer subtypes. A subset of HER2+ breast cancers with amplification of the TFAP2C gene locus becomes addicted to AP-2γ. Herein, we sought to define AP-2γ gene targets in HER2+ breast cancer and identify genes accounting for physiologic effects of growth and invasiveness regulated by AP-2γ. Comparing HER2+ 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-2γ and that contributed to growth and invasiveness. Pathway analysis implicated the MAPK13/p38δ and retinoic acid regulatory nodes, which were confirmed to display divergent responses in different HER2+ cancer lines. To confirm the clinical relevance of the genes identified, the AP-2γ gene signature was found to be highly predictive of outcome in patients with HER2+ breast cancer. We conclude that AP-2γ regulates a set of genes in HER2+ breast cancer that drive cancer growth and invasiveness. The AP-2γ gene signature predicts outcome of patients with HER2+ 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-2γ in HER2+ breast cancer that drive proliferation and invasion were identified and provided a gene signature that is predictive of outcome in HER2+ breast cancer.

Intraoperative Radiotherapy for Breast Cancer Treatment in a Rural Community.

BACKGROUND: Access to health care poses particular challenges for patients living in rural communities. Intraoperative radiotherapy (IORT) offers a treatment alternative to traditional whole-breast radiation therapy (WBRT) for select patients. This study aimed to analyze the use of IORT for patients undergoing breast-conserving surgery at an academic institution located in a rural state. METHODS: A retrospective review analyzed all patients at a single institution with a diagnosis of ductal carcinoma in situ (DCIS) or invasive breast cancer from April 2012 to January 2017 who were undergoing breast-conserving surgery with either IORT or WBRT. Student's t test or Fisher's exact test was used to make statistical comparisons. RESULTS: Patients undergoing IORT (n = 117) were significantly older than patients treated with WBRT (n = 191) (65.6 vs 58.6 years; p < 0.001) and had smaller tumors on both preoperative imaging (1.04 vs 1.66 cm; p < 0.05) and final pathology (0.99 vs 1.48 cm; p < 0.05). Patients receiving IORT lived farther from the treating facility than patients treated with WBRT (67.2 vs 30.8 miles; p < 0.05). To account for biases created in the IORT selection criteria, subgroup analysis was performed for women receiving WBRT who fulfilled IORT selection criteria, and distance traveled remained significant (67.2 vs 31.4 miles; p < 0.05). Neither recurrence nor survival differed between the IORT and WBRT groups. Medicare reimbursement for IORT was approximately 50% more than for WBRT. CONCLUSIONS: 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.