PMID- 20030805
OWN - NLM
STAT- MEDLINE
DCOM- 20100429
LR  - 20220318
IS  - 1476-4598 (Electronic)
IS  - 1476-4598 (Linking)
VI  - 8
DP  - 2009 Dec 23
TI  - Cooperation of Notch and Ras/MAPK signaling pathways in human breast 
      carcinogenesis.
PG  - 128
LID - 10.1186/1476-4598-8-128 [doi]
AB  - BACKGROUND: Recent studies have implicated aberrant Notch signaling in breast 
      cancers. Yet, relatively little is known about the pattern of expression of 
      various components of the Notch pathway, or its mechanism of action. To better 
      understand the role of the Notch pathway in breast cancer, we have undertaken a 
      detailed expression analysis of various Notch receptors, their ligands, and 
      downstream targets at different stages of breast cancer progression. RESULTS: We 
      report here that there is a general increase in the expression levels of Notch 1, 
      2, 4, Jagged1, Jagged2, and Delta-like 4 proteins in breast cancers, with 
      simultaneous upregulation of multiple Notch receptors and ligands in a given 
      cancer tissue. While Notch3 and Delta-like1 were undetectable in normal tissues, 
      moderate to high expression was detected in several cancers. We detected the 
      presence of active, cleaved Notch1, along with downstream targets of the Notch 
      pathway, Hes1/Hes5, in approximately 75% of breast cancers, clearly indicating 
      that in a large proportion of breast cancers Notch signaling is aberrantly 
      activated. Furthermore, we detected cleaved Notch1 and Hes1/5 in early precursors 
      of breast cancers - hyperplasia and ductal carcinoma in situ - suggesting that 
      aberrant Notch activation may be an early event in breast cancer progression. 
      Mechanistically, while constitutively active Notch1 alone failed to transform 
      immortalized breast cells, it synergized with the Ras/MAPK pathway to mediate 
      transformation. This cooperation is reflected in vivo, as a subset of cleaved 
      Notch positive tumors additionally expressed phopsho-Erk1/2 in the nuclei. Such 
      cases exhibited high node positivity, suggesting that Notch-Ras cooperation may 
      lead to poor prognosis. CONCLUSIONS: High level expression of Notch receptors and 
      ligands, and its increased activation in several breast cancers and early 
      precursors, places Notch signaling as a key player in breast cancer pathogenesis. 
      Its cooperation with the Ras/MAPK pathway in transformation offers combined 
      inhibition of the two pathways as a new modality for breast cancer treatment.
FAU - Mittal, Suruchi
AU  - Mittal S
AD  - Department of Molecular Reproduction, Development and Genetics, Indian Institute 
      of Science, Bangalore 560 012, Karnataka, India. suruchi.mittal@gmail.com
FAU - Subramanyam, Deepa
AU  - Subramanyam D
FAU - Dey, Devaveena
AU  - Dey D
FAU - Kumar, Rekha V
AU  - Kumar RV
FAU - Rangarajan, Annapoorni
AU  - Rangarajan A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20091223
PL  - England
TA  - Mol Cancer
JT  - Molecular cancer
JID - 101147698
RN  - 0 (Ligands)
RN  - 0 (Receptors, Notch)
RN  - EC 3.6.5.2 (Oncogene Protein p21(ras))
SB  - IM
MH  - Breast Neoplasms/enzymology/*metabolism/pathology
MH  - Cell Transformation, Neoplastic
MH  - Disease Progression
MH  - Humans
MH  - Ligands
MH  - *MAP Kinase Signaling System
MH  - Oncogene Protein p21(ras)/*metabolism
MH  - Receptors, Notch/*metabolism
MH  - *Signal Transduction
PMC - PMC2809056
EDAT- 2009/12/25 06:00
MHDA- 2010/04/30 06:00
PMCR- 2009/12/23
CRDT- 2009/12/25 06:00
PHST- 2009/08/18 00:00 [received]
PHST- 2009/12/23 00:00 [accepted]
PHST- 2009/12/25 06:00 [entrez]
PHST- 2009/12/25 06:00 [pubmed]
PHST- 2010/04/30 06:00 [medline]
PHST- 2009/12/23 00:00 [pmc-release]
AID - 1476-4598-8-128 [pii]
AID - 10.1186/1476-4598-8-128 [doi]
PST - epublish
SO  - Mol Cancer. 2009 Dec 23;8:128. doi: 10.1186/1476-4598-8-128.