Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.12.2 (
MEK
)
18,161
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Breast cancer remains a complex disease resulting in high mortality in women. A subset of cancer stem cell (CSC)-like cells expressing aldehyde dehydrogenase 1 (ALDH1) and SOX2/OCT4 are implicated in aggressive biology of specific subtypes of breast cancer. Targeting these populations in breast tumors remain challenging. We examined xenografts from three poorly studied triple negative (TN) breast cancer cells (MDA-MB-468, HCC70 and HCC1806) as well as HMLE
HRASV12
for stem cell (SC)-specific proteins, proliferation pathways and dual-specific phosphatases (DUSPs) by quantitative real-time PCR (qRT-PCR), immunoblot analysis and immunohistochemistry. We found that pERK1/2 remained suppressed in TN xenografts examined at various stages of growth, while the levels of pp38 MAPK and pAKT was upregulated. We found that DUSP was involved in the suppression of pERK1/2, which was
MEK1
/2 independent. Our
in vitro
assays, using HMLE
HRASV12
xenografts as a positive control, confirmed increased phosphatase activity that specifically influenced pERK1/2 but not pp38MAPK or pJNK levels. Family members of DUSPs examined, showed increase in
DUSP9
expression in TN xenografts. Increased
DUSP9
expression in xenografts was consistently associated with upregulation of SC-specific proteins, ALDH1 and SOX2/OCT4. HRAS driven HMLE
HRASV12
xenografts as well as mammospheres from TN breast cancer cells showed inverse relationship between pERK1/2 and increased expression of
DUSP9
and CSC traits. In addition, treatment
in vitro
, with
MEK1
/2 inhibitor, PD 98059, reduced pERK1/2 levels and increased
DUSP9
and SC-specific proteins. Depletion of subsets of SOX2/OCT4 by fluorescence-activated cell sorting (FACS), as well as pharmacological and genetic reduction of
DUSP9
levels influenced ALDH1 and SOX2/OCT4 expression and reduced mammosphere growth
in vitro
as well as tumor growth
in vivo
. Collectively our data support the possibility that
DUSP9
contributed to stem cell-like cells that could influence TN breast tumor growth. Conclusion: Our study shows that subsets of TN breast cancers with
MEK1
/2 independent reduced pERK1/2 levels will respond less to
MEK1
/2 inhibitors, thereby questioning their therapeutic efficacy. Our study also demonstrates context-dependent
DUSP9
-mediated reduced pERK1/2 levels could influence stem cell-like traits in TN breast tumors. Therefore, targeting
DUSP9
could be an attractive target for improved clinical outcome in a subset of basal-like breast cancers.
...
PMID:DUSP9-mediated reduction of pERK1/2 supports cancer stem cell-like traits and promotes triple negative breast cancer. 3316 85
