title: Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches.
abstract: High expression of Notch-1 and Jagged-1 mRNA correlates with poor prognosis in breast cancer. Elucidating the cross-talk between Notch and other major breast cancer pathways is necessary to determine which patients may benefit from Notch inhibitors, which agents should be combined with them, and which biomarkers indicate Notch activity in vivo. We explored expression of Notch receptors and ligands in clinical specimens, as well as activity, regulation, and effectors of Notch signaling using cell lines and xenografts. Ductal and lobular carcinomas commonly expressed Notch-1, Notch-4, and Jagged-1 at variable levels. However, in breast cancer cell lines, Notch-induced transcriptional activity did not correlate with Notch receptor levels and was highest in estrogen receptor alpha-negative (ERalpha(-)), Her2/Neu nonoverexpressing cells. In ERalpha(+) cells, estradiol inhibited Notch activity and Notch-1(IC) nuclear levels and affected Notch-1 cellular distribution. Tamoxifen and raloxifene blocked this effect, reactivating Notch. Notch-1 induced Notch-4. Notch-4 expression in clinical specimens correlated with proliferation (Ki67). In MDA-MB231 (ERalpha(-)) cells, Notch-1 knockdown or gamma-secretase inhibition decreased cyclins A and B1, causing G(2) arrest, p53-independent induction of NOXA, and death. In T47D:A18 (ERalpha(+)) cells, the same targets were affected, and Notch inhibition potentiated the effects of tamoxifen. In vivo, gamma-secretase inhibitor treatment arrested the growth of MDA-MB231 tumors and, in combination with tamoxifen, caused regression of T47D:A18 tumors. Our data indicate that combinations of antiestrogens and Notch inhibitors may be effective in ERalpha(+) breast cancers and that Notch signaling is a potential therapeutic target in ERalpha(-) breast cancers.
authors.affiliation: Breast Cancer Program and Skin Cancer Program, Cardinal Bernardin Cancer Center, Loyola University Chicago.
authors.forename: Paola
authors.initials: P
authors.lastname: Rizzo
authors.forename: Haixi
authors.initials: H
authors.lastname: Miao
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: D'Souza
authors.forename: Clodia
authors.initials: C
authors.lastname: Osipo
authors.forename: Lynda L
authors.initials: LL
authors.lastname: Song
authors.forename: Jieun
authors.initials: J
authors.lastname: Yun
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhao
authors.forename: Joaquina
authors.initials: J
authors.lastname: Mascarenhas
authors.forename: Debra
authors.initials: D
authors.lastname: Wyatt
authors.forename: Giovanni
authors.initials: G
authors.lastname: Antico
authors.forename: Lu
authors.initials: L
authors.lastname: Hao
authors.forename: Katharine
authors.initials: K
authors.lastname: Yao
authors.forename: Prabha
authors.initials: P
authors.lastname: Rajan
authors.forename: Chindo
authors.initials: C
authors.lastname: Hicks
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Siziopikou
authors.forename: Suzanne
authors.initials: S
authors.lastname: Selvaggi
authors.forename: Amina
authors.initials: A
authors.lastname: Bashir
authors.forename: Deepali
authors.initials: D
authors.lastname: Bhandari
authors.forename: Adriano
authors.initials: A
authors.lastname: Marchese
authors.forename: Urban
authors.initials: U
authors.lastname: Lendahl
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Qin
authors.forename: Debra A
authors.initials: DA
authors.lastname: Tonetti
authors.forename: Kathy
authors.initials: K
authors.lastname: Albain
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Nickoloff
authors.forename: Lucio
authors.initials: L
authors.lastname: Miele
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D016503:Drug Delivery Systems; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage; D020239:Receptor Cross-Talk / Q000502:physiology*; D051881:Receptor, Notch1 / Q000378:metabolism; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; C497761:NOTCH1 protein, human; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D004958:Estradiol