Overexpression of ligase defective E6-associated protein, E6-AP, results in mammary tumorigenesis

Abstract

E6-associated protein (E6-AP) is a dual function protein. It acts as an E3 ubiquitin-protein ligase enzyme and coactivator of steroid hormone receptors such as estrogen (ERα) and progesterone (PR) receptors. It promotes the degradation of ERα and PR through the ubiquitin-proteasome pathway. Furthermore, it has been shown that the levels of E6-AP are inversely associated with that of ERα in human breast tumors. But the role of wild-type human E6-AP and its ubiquitin-protein ligase activity in mammary tumorigenesis is still unknown. To investigate this role, the authors utilized transgenic mice lines that specifically overexpress either the wild-type human E6-AP (E6-AP(WT)) or the ubiquitin-protein ligase defective E6-AP that contains C833S mutation (E6-AP(C833S)) in the mammary gland. To further substantiate the role of E6-AP in the development of breast tumorigenesis, it was also examined the expression of E6-AP in a large cohort of human breast cancer samples. The transgenic mice that overexpress wild-type E6-AP (E6-AP(WT)) fail to develop mammary tumors. Unlike the E6-AP(WT) mice, the E6-AP(C833S) mice that overexpress ubiquitin-protein ligase defective E6-AP protein develop mammary hyperplasia with a median latency of 18 months. These observations suggest that the inactivation of the ubiquitin-protein ligase function of E6-AP is sufficient to initiate the process of mammary tumor development. Furthermore, the data also suggests that E6-AP exerts its effects on target cells by modulating the protein levels and functions of ERα and PR. In addition, it was found in human breast cancer patients that the level of E6-AP is decreased in invasive breast tumors compared to normal breast tissue. Moreover, the authors also show that the survival patterns for E6-AP negative patients were worse compared to E6-AP positive patients. Taken together, these data suggests that E6-AP may act as a tumor suppressor in breast.

The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling

“…Reduced E6AP expression correlates with more invasive breast carcinomas (24). Taken together, these previous findings support a tumor-suppressive function for E6AP in breast cancer.…”

“…Importantly, Ras-transformed E6AP-KO MEFs form tumors in mice that are more invasive than their WT counterparts, indicating a role for E6AP in controlling tumor dissemination (23). In addition, recent studies indicate a role for E6AP in human breast cancer, where invasive ductal carcinoma has lower E6AP protein levels than normal breast in situ (24). Here, we report that loss of E6AP enhances invasiveness of the cells and their ability to seed distant metastases.…”

Steroid Hormone Receptor Coregulators in Endocrine Cancers

“…Thus determining PR-B level alteration through ubiquitin proteasome degradation via E6AP ultimately controlled part of physiologic mammary gland development (77). Further evaluation of this ligase function defective E6AP established it to be a sufficient condition for mammary tumorigenesis in mice when contrasted to a wild type E6AP, which failed to generate mammary tumors (78). These several findings support a clinical correlation, where E6AP negative patients displayed a worse prognosis relative to patients expressing the protein (78).…”

“…Further evaluation of this ligase function defective E6AP established it to be a sufficient condition for mammary tumorigenesis in mice when contrasted to a wild type E6AP, which failed to generate mammary tumors (78). These several findings support a clinical correlation, where E6AP negative patients displayed a worse prognosis relative to patients expressing the protein (78). A breast cancer effect by E6AP distinct in direction from those previously mentioned was investigated by Lochab et al (79).…”

Pin1 modulates ERα levels in breast cancer through inhibition of phosphorylation-dependent ubiquitination and degradation

“…E6AP protein expression is decreased in human invasive BC, and overexpression of ubiquitin-ligase defective E6AP initiates mammary tumor development, implicating an important role of E6AP ligase activity in tumor suppression 60–61 . E6AP also interacts with other nuclear receptors, partially because it contains three signature LXXLL motifs (nuclear receptor interacting motifs) that bind to the CTD of nuclear receptors 31 .…”