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2016 ; 7
(44
): 71580-71593
Nephropedia Template TP
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English Wikipedia
Blockade of the Hedgehog pathway downregulates estrogen receptor alpha signaling
in breast cancer cells
#MMPMID27689403
Diao Y
; Azatyan A
; Rahman MF
; Zhao C
; Zhu J
; Dahlman-Wright K
; Zaphiropoulos PG
Oncotarget
2016[Nov]; 7
(44
): 71580-71593
PMID27689403
show ga
Anti-estrogen treatment, exemplified by tamoxifen, is a well-established adjuvant
therapy for estrogen receptor alpha (ER?)-positive breast cancer. However, the
effectiveness of this drug is limited due to the development of resistance. The
Hedgehog (HH) signaling pathway is critical in embryonic development, and
aberrant activation of this transduction cascade is linked to various
malignancies. However, it remains unclear whether HH signaling is activated in
human breast cancer and related to tamoxifen resistance. Deciphering how this
pathway may be involved in breast cancer is a crucial step towards the
establishment of targeted combinatorial treatments for this disease. Here, we
show that the expression of the HH signaling effector protein GLI1 is higher in
tamoxifen resistant compared to sensitive cells. Tamoxifen resistant cells have
stronger ER? transcriptional activity relative to sensitive cells, even though
the ER? expression is similar in both cell types. Knockdown of GLI1 attenuates
cell proliferation and reduces ER? transcriptional activity in both sensitive and
resistant cells, irrespective of estrogen stimulation. Combinatorial treatment of
tamoxifen and the GLI antagonist GANT61 further suppresses the growth of
sensitive and resistant cells relative to administration of only tamoxifen, and
this was irrespective of estrogen stimulation. Moreover, a positive correlation
between GLI1 and ER? expression was identified in breast cancer samples.
Additionally, high GLI1 expression predicted worse distant metastasis-free
survival in breast cancer patients. These data suggest that the HH pathway may be
a new candidate for therapeutic targeting and prognosis in ER?-positive breast
cancer.
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