Journal
ONCOTARGET
Volume 7, Issue 44, Pages 71580-71593Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.12259
Keywords
glioma associated oncogene; GLI1; tamoxifen; drug targeting; GANT61
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Funding
- Swedish Childhood Cancer Foundation
- AFA Insurance
- China Scholarship Council
- Karolinska Institutet Doctoral (KID) funding program
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Anti-estrogen treatment, exemplified by tamoxifen, is a well-established adjuvant therapy for estrogen receptor alpha (ERa)-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 ERa transcriptional activity relative to sensitive cells, even though the ERa expression is similar in both cell types. Knockdown of GLI1 attenuates cell proliferation and reduces ERa 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 ERa 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 ERa-positive breast cancer.
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