Blockade of the Hedgehog pathway downregulates estrogen receptor alpha signaling in breast cancer cells.
Anti-estrogen treatment, exemplified by tamoxifen, is a well-established adjuvant therapy for estrogen receptor alpha (ERα)-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 ERα transcriptional activity relative to sensitive cells, even though the ERα expression is similar in both cell types. Knockdown of GLI1 attenuates cell proliferation and reduces ERα 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 ERα 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 ERα-positive breast cancer.
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Yumei
Y
Diao
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Ani
A
Azatyan
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Mohammed Ferdous-Ur
MF
Rahman
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Chunyan
C
Zhao
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Jian
J
Zhu
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Karin
K
Dahlman-Wright
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Peter G
PG
Zaphiropoulos
D001943:Breast Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D049109:Cell Proliferation; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000502:physiology; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D061986:MCF-7 Cells; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020218:Response Elements; D015398:Signal Transduction / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1 / Q000502:physiology
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; C551027:GANT 61; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D011725:Pyridines; D011743:Pyrimidines; D000071676:Zinc Finger Protein GLI1; D013629:Tamoxifen
GANT61; GLI1; drug targeting; glioma associated oncogene; tamoxifen
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