Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches.
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.
Rizzo
Paola
P
Breast Cancer Program and Skin Cancer Program, Cardinal Bernardin Cancer Center, Loyola University Chicago.
Miao
Haixi
H
D'Souza
Gwendolyn
G
Osipo
Clodia
C
Song
Lynda L
LL
Yun
Jieun
J
Zhao
Huiping
H
Mascarenhas
Joaquina
J
Wyatt
Debra
D
Antico
Giovanni
G
Hao
Lu
L
Yao
Katharine
K
Rajan
Prabha
P
Hicks
Chindo
C
Siziopikou
Kalliopi
K
Selvaggi
Suzanne
S
Bashir
Amina
A
Bhandari
Deepali
D
Marchese
Adriano
A
Lendahl
Urban
U
Qin
Jian-Zhong
JZ
Tonetti
Debra A
DA
Albain
Kathy
K
Nickoloff
Brian J
BJ
Miele
Lucio
L
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
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