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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.

SUBMITTER: Rizzo P

PROVIDER: S-EPMC4445363 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches.

Rizzo Paola P 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

Cancer research 20080701 13

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 ...[more]

PMID: 18593923

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Project description:This study aimed to characterize estrogen receptor expression and signaling in head and neck squamous cell carcinoma (HNSCC) cell lines and patient tissues, and to evaluate estrogen receptor and epidermal growth factor (EGF) receptor (EGFR) cross-activation in HNSCC.Estrogen receptor expression and signaling in HNSCC cell lines were assessed by immunoblotting. In vitro proliferation and invasion were evaluated in HNSCC cell lines in response to estrogen receptor and EGFR ligands or inhibitors. Estrogen receptor and EGFR protein expression in patient tissues was assessed by immunohistochemical staining.Phospho-mitogen-activated protein kinase (P-MAPK) levels were significantly increased following combined estrogen and EGF treatment. Treatment of HNSCC cells with estrogen and EGF significantly increased cell invasion compared with either treatment alone, whereas inhibiting these two pathways resulted in reduced invasion compared with inhibiting either pathway alone. EGFR (P = 0.008) and nuclear estrogen receptor alpha (ER alpha(nuc); P < 0.001) levels were significantly increased in HNSCC tumors (n = 56) compared with adjacent mucosa (n = 30), whereas nuclear estrogen receptor beta (ER beta(nuc)) levels did not differ (P = 0.67). Patients with high ER alpha(nuc) and EGFR tumor levels had significantly reduced progression-free survival compared with patients with low tumor ER alpha(nuc) and EGFR levels (hazards ratio, 4.09; P = 0.01; Cox proportional hazards). In contrast, high ER beta(nuc) tumor levels were not associated with reduced progression-free survival alone or when combined with EGFR.ER alpha and ER beta were expressed in HNSCC, and stimulation with estrogen receptor ligands resulted in both cytoplasmic signal transduction and transcriptional activation. Estrogen receptor and EGFR cross-talk was observed. Collectively, these studies indicate that estrogen receptor and EGFR together may contribute to HNSCC development and disease progression.

Project description:PurposeThe interplay between estrogen receptor (ER) and erbB tyrosine-kinase receptors (RTK) impacts growth and progression of ER-positive (ER+)/HER2-positive (HER2+) breast cancer and generates mitogenic signals converging onto the Cyclin-D1/CDK4/6 complex. We probed this cross-talk combining endocrine-therapy (fulvestrant), dual HER2-blockade (trastuzumab and pertuzumab), and CDK4/6-inhibition (palbociclib; PFHPert).Experimental designCytotoxic drug effects, interactions, and pharmacodynamics were studied after 72 hours of treatment and over 6 more days of culture after drug wash-out in three ER+/HER2+, two HER2low, and two ER-negative (ER-)/HER2+ breast cancer cell lines. We assessed gene-expression dynamic and association with Ki67 downregulation in 28 patients with ER+/HER2+ breast cancer treated with neoadjuvant PFHPert in NA-PHER2 trial (NCT02530424).ResultsIn vitro, palbociclib and/or fulvestrant induced a functional activation of RTKs signalling. PFHPert had additive or synergistic antiproliferative activity, interfered with resistance mechanisms linked to the RTKs/Akt/MTORC1 axis and induced sustained senescence. Unexpected synergism was found in HER2low cells. In patients, Ki67 downregulation at week 2 and surgery were significantly associated to upregulation of senescence-related genes (P = 7.7E-4 and P = 1.8E-4, respectively). Activation of MTORC1 pathway was associated with high Ki67 at surgery (P = 0.019).ConclusionsResistance associated with the combination of drugs targeting ER and HER2 can be bypassed by cotargeting Rb, enhancing transition from quiescence to sustained senescence. MTORC1 pathway activation is a potential mechanism of escape and RTKs functional activation may be an alternative pathway for survival also in ER+/HER2low tumor. PFHPert combination is an effective chemotherapy-free regimen for ER+/HER2+ breast cancer, and the mechanistic elucidation of sensitivity/resistance patterns may provide insights for further treatment refinement.

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Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches.

Publications

Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches.

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