Role of the BCA2 Ubiquitin E3 Ligase in Hormone Responsive Breast Cancer

Abstract

The BCA2 protein contains a RING H2 finger and a Zn finger near the N-terminus and has E3 ligase activity. RING finger proteins play critical roles in mediating the transfer of ubiquitin and ubiquitin like modifiers to heterologous substrates as well as to the RING finger proteins themselves. Protein modification by ubiquitin and small ubiquitin-related modifier (SUMO) plays a pivotal role in protein homeostasis and is critical to regulating basic cellular processes such as proliferation, differentiation, apoptosis, intracellular signaling, and gene-transcriptional regulation. The addition of ubiquitin or SUMO can modulate the ability of proteins to interact with their partners, alter their patterns of sub-cellular localization and control their stability. It is clear that SUMO influences many different biological processes however recent data suggest that it is specifically important in the regulation of transcription. BCA2 is an E3 ligase that interacts with the SUMO conjugating enzyme Ubc9. It could therefore function as an E3 in the sumoylation of various transcription factors. We have found that the BCA2 is co-expressed with the estrogen receptor in 74% of ER-positive invasive ductal carcinomas from a 635 member breast cancer cohort (p = 0.004). At the cellular level, BCA2 co-localizes with ER and it appears that at the transcriptional level BCA2 mRNA expression is regulated by estrogen. Bioinformatic analysis of the BCA2 promoter region revealed ER and PR binding sites as well as that of other more general transcription factors. The data presented here provides an overview of the potential involvement of the BCA2 in hormone responsive breast cancer and opens up avenues that should be exploited to better understand the regulation of ER expression, growth of breast cancer cells, and the importance of BCA2.

Regulation of DNA Damage Response by Estrogen Receptor β-Mediated Inhibition of Breast Cancer Associated Gene 2

“…It was found that Erb-041 inhibited chromatin association of ERα, leading to the reduced expression of BCA2. In support of our observation, ERα has been reported to bind to the estrogen response element of BCA2 and promote the gene transcription of p21 [12,29]. Through the association with cyclin−cdk complexes, p21 mediates cell cycle checkpoints at G1/S and G2/M transitions, thus permitting DNA repair to take place [30,31].…”

“…The correlation between the nuclear expression of BCA2 and positive ER status suggests that BCA2 may be involved in the adaptation of estrogen-responsive cancers to chronic replication stress by upregulating the cells’ DNA repair capability [11]. BCA2 has been characterized as an ubiquitin E3 ligase, RING-finger protein (RNF115), or Rab7-interacting RING-finger protein (Rabring7) that is overexpressed in more than 50 percent of breast tumors, including ER-negative breast cancers [12]. It is known that BCA2 promotes breast cancer development in association with ubiquitin-mediated degradation of p21 Waf1/Cip1 via its E3 ubiquitin ligase activity [13].…”

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

“…Interestingly, RNF115 [also known as breast cancer-associated gene 2 (BCA2)] was strongly rhythmic in our study. RNF115 is another ubiquitin E3 ligase that is strongly associated with increased tumor growth, particularly in response to estrogen (43). Many studies have found significant correlations between disrupted circadian rhythms and increased risk for certain cancers, including breast cancer (44).…”

Signaling functions of ubiquitin in the 17β-estradiol (E2):estrogen receptor (ER) α network

“…As a consequence, targeting the Ub system in breast cancer is becoming an appealing pharmacological option especially in light of the fact that the expression of several E 3 Ub ligases often correlates with ER␣ expression [59,[61][62][63]. Indeed, ER␣-positive breast cancers are treated with drugs that destroy ER␣ thus reducing receptor tumor levels and tumor responsiveness to circulating E2 [64].…”