Cancer constitutes a set of diseases with heterogeneous molecular pathologies. However, there are a number of universal aberrations common to all cancers, one of these being the epigenetic silencing of tumor suppressor genes (TSGs). The silencing of TSGs is thought to be an early, driving event in the oncogenic process. With this in consideration, great efforts have been made to develop small molecules aimed at the restoration of TSGs in order to limit tumor cell proliferation and survival. However, the molecular forces that drive the broad epigenetic reprogramming and transcriptional repression of these genes remain ill-defined. Undoubtedly, understanding the molecular underpinnings of transcriptionally silenced TSGs will aid us in our ability to reactivate these key anti-cancer targets. Here, we describe what we consider to be the five most logical molecular mechanisms that may account for this widely observed phenomenon: 1) ablation of transcription factor binding, 2) overexpression of DNA methyltransferases, 3) disruption of CTCF binding, 4) elevation of EZH2 activity, 5) aberrant expression of long non-coding RNAs. The strengths and weaknesses of each proposed mechanism is highlighted, followed by an overview of clinical efforts to target these processes.

A new role for the mutlifunctional protein CTCF in the repair of DNA double-strand breaks is discovered.

The selective estrogen receptor downregulator (SERD) fulvestrant can be used as second-line treatment for patients relapsing after treatment with tamoxifen, a selective estrogen receptor modulator (SERM). Unlike tamoxifen, SERDs are devoid of partial agonist activity. While the full antiestrogenicity of SERDs may result in part from their capacity to downregulate levels of estrogen receptor alpha (ER␣) through proteasome-mediated degradation, SERDs are also fully antiestrogenic in the absence of increased receptor turnover in HepG2 cells. Here we report that SERDs induce the rapid and strong SUMOylation of ER␣ in ER␣-positive and -negative cell lines, including HepG2 cells. Four sites of SUMOylation were identified by mass spectrometry analysis. In derivatives of the SERD ICI164,384, SUMOylation was dependent on the length of the side chain and correlated with full antiestrogenicity. Preventing SUMOylation by the overexpression of a SUMO-specific protease (SENP) deSUMOylase partially derepressed transcription in the presence of full antiestrogens in HepG2 cells without a corresponding increase in activity in the presence of agonists or of the SERM tamoxifen. Mutations increasing transcriptional activity in the presence of full antiestrogens reduced SUMOylation levels and suppressed stimulation by SENP1. Our results indicate that ER␣ SUMOylation contributes to full antiestrogenicity in the absence of accelerated receptor turnover. E strogens, mainly 17␤-estradiol (E2), play a crucial role in normal breast development but also contribute to mammary tumorigenesis. Antiestrogens (AEs) used for breast cancer treatment and prevention, such as tamoxifen (Tam), raloxifene (Ral), or fulvestrant (9, 17, 52, 63), block the proliferative effects of estrogens on breast epithelial and carcinoma cells by competing for estrogen receptors (ERs) (ER␣ and ER␤). Similar to other nuclear receptors, ERs activate gene transcription by binding to specific DNA sites and recruiting transcriptional coactivators in a liganddependent manner (13,40,41,70,85).AEs prevent ER activation through the induction of an altered conformation of the receptor ligand binding domain (LBD) that suppresses the recruitment of coactivators (8,66,79) and/or increases the recruitment of corepressors (23,34,45,61,77,83,94). However, selective ER modulators (SERMs) (which include Tam and Ral) have partial agonist activity in a tissue-and gene-specific manner. For example, both have estrogenic effects on bone mass (6), and Tam has estrogenic effects on the uterus (2,5,21,88,90), while Ral does not cause uterine hypertrophy (6). Tam and, to a lesser extent, Ral also have partial agonist activity in breast cancer cells in a gene-specific manner (22). The tissue-specific recruitment of coactivators and corepressors is thought to underlie selective partial agonist activity, and alterations in the expression patterns or activity of ER cofactors in breast cancer cells could contribute to the development of resistance to AE-based therapy (23,37,38,45,77,81,82).Other AEs,...