title: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Braman Family Breast Cancer Institute (M-877)/Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, BRB Building, Room 723, 1501 NW 10th Avenue, Miami, FL 33136, USA.
authors.forename: Sivapriya
authors.initials: S
authors.lastname: Ramamoorthy
authors.forename: Rozina
authors.initials: R
authors.lastname: Tufail
authors.forename: Jimmy El
authors.initials: JE
authors.lastname: Hokayem
authors.forename: Mercy
authors.initials: M
authors.lastname: Jorda
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Zizi
authors.initials: Z
authors.lastname: Reis
authors.forename: Zafar
authors.initials: Z
authors.lastname: Nawaz
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000201:enzymology / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D055633:Immune System Phenomena; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D053208:Kaplan-Meier Estimate; D008321:Mammary Glands, Animal / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D011980:Receptors, Progesterone; D025521:Tumor Suppressor Proteins; C097314:progesterone receptor B; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases