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2018 ; 9
(51
): 29727-29742
Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
MGMT inhibition in ER positive breast cancer leads to CDC2, TOP2A, AURKB, CDC20,
KIF20A, Cyclin A2, Cyclin B2, Cyclin D1, ER? and Survivin inhibition and enhances
response to temozolomide
#MMPMID30038716
Bobustuc GC
; Kassam AB
; Rovin RA
; Jeudy S
; Smith JS
; Isley B
; Singh M
; Sassoon D
; Srivenugopal KS
; Konduri SD
Oncotarget
2018[Jul]; 9
(51
): 29727-29742
PMID30038716
show ga
The DNA damage repair enzyme, O(6)-methylguanine DNA methyltransferase (MGMT) is
overexpressed in breast cancer, correlating directly with estrogen receptor (ER)
expression and function. In ER negative breast cancer the MGMT promoter is
frequently methylated. In ER positive breast cancer MGMT is upregulated and
modulates ER function. Here, we evaluate MGMT's role in control of other
clinically relevant targets involved in cell cycle regulation during breast
cancer oncogenesis. We show that O(6)-benzylguanine (BG), an MGMT inhibitor
decreases CDC2, CDC20, TOP2A, AURKB, KIF20A, cyclin B2, A2, D1, ER? and survivin
and induces c-PARP and p21 and sensitizes ER positive breast cancer to
temozolomide (TMZ). Further, siRNA inhibition of MGMT inhibits CDC2, TOP2A,
AURKB, KIF20A, Cyclin B2, A2 and survivin and induces p21. Combination of BG+TMZ
decreases CDC2, CDC20, TOP2A, AURKB, KIF20A, Cyclin A2, B2, D1, ER? and survivin.
Temozolomide alone inhibits MGMT expression in a dose and time dependent manner
and increases p21 and cytochrome c. Temozolomide inhibits transcription of TOP2A,
AURKB, KIF20A and does not have any effect on CDC2 and CDC20 and induces p21.
BG+/-TMZ inhibits breast cancer growth. In our orthotopic ER positive breast
cancer xenografts, BG+/-TMZ decreases ki-67, CDC2, CDC20, TOP2A, AURKB and
induces p21 expression. In the same model, BG+TMZ combination inhibits breast
tumor growth in vivo compared to single agent (TMZ or BG) or control. Our results
show that MGMT inhibition is relevant for inhibition of multiple downstream
targets involved in tumorigenesis. We also show that MGMT inhibition increases ER
positive breast cancer sensitivity to alkylator based chemotherapy.