Gli1 promotes cell survival and is predictive of a poor outcome in ERα-negative breast cancer

Abstract

Gli1 is a transcription factor and oncogene with documented roles in the progression of several cancer types, including cancers of the skin and pancreas. The contribution of Gli1 to the progression of breast cancer is less established. In order to investigate the functional impact of Gli1 in breast cancer, expression of Gli1 and its contribution to cell growth was assessed in breast cancer cell lines. These in vitro results were compared to expression of Gli1, determined by immunohistochemistry, in 171 breast cancers. In these cancers, the association of Gli1 with expression of estrogen receptor α (ERα) and progesterone receptor (PR), ErbB2, p53, the rate of proliferation, and clinicopathologic parameters and outcome was assessed. Expression of Gli1 and ERα mRNA was strongly correlated in ERα-positive cell lines (r = 0.999). Treatment with estrogen increased expression of Gli1 in 2 of 3 ERα-positive cell lines; this increase was prevented by treatment with the ERα-specific antagonist MPP. Silencing of Gli1 by shRNA markedly reduced the survival of two ERα-negative cell lines, but caused only a modest reduction in ERα-positive cell lines. In breast cancer tissues, cancers with nuclear localization of Gli1 had a higher ERα (P=0.027) and lower p53 expression (P=0.017) than those without nuclear localization of Gli1. However, nuclear localization of Gli1 was predictive of a poorer cancer-specific survival in ERα-negative, including triple negative, cancers (P = 0.005), but not ERα-positive cancers. In conclusion, we demonstrate a positive association between expression of Gli1 and ERα; however, our data indicate a greater functional effect of Gli1 in ERα-negative cancers.

A Synthetic Triterpenoid CDDO-Im Inhibits Tumorsphere Formation by Regulating Stem Cell Signaling Pathways in Triple-Negative Breast Cancer

“…The high expression level of GLI1, the key downstream effector of the Hedgehog signaling pathway, is associated with unfavorable overall survival in cancer patients [48], [49]. Moreover, a recent study demonstrated that GLI1 was a central regulator of cancer stem cells in triple-negative breast cancer [50].…”

New paradigms for the Hedgehog signaling network in mammary gland development and breast Cancer

“…PTCH protein expression showed a positive correlation with ER positive, but not PR positive breast cancers [81]. Gli1 (nuclear GLI1 protein) and ERα mRNA and protein expression correlate in many patient tumors and breast cancer cell lines [86,98–100]. Estradiol treatment can induce GLI1 mRNA, and nuclear localization of GLI1 in ER positive breast cancer cell lines to promote proliferation, survival, and invasiveness [86,98,100].…”

“…Gli1 (nuclear GLI1 protein) and ERα mRNA and protein expression correlate in many patient tumors and breast cancer cell lines [86,98–100]. Estradiol treatment can induce GLI1 mRNA, and nuclear localization of GLI1 in ER positive breast cancer cell lines to promote proliferation, survival, and invasiveness [86,98,100]. On the other hand, a different study reported that Gli1 attenuated the mitogenic response of breast cancer cells to estradiol [92].…”

“…Additionally, nuclear GLI1 protein was correlated with poorer patient disease-free and overall survival, higher tumor stage, and increased lymph node positivity [109,110]. GLI1 also predicted reduced pathological complete response in hormone receptor negative breast cancers [100,110]. However, in a different report, nuclear GLI1 correlates with triple negative breast cancer, and does not predict worse patient survival in ER positive cancer [100].…”

“…GLI1 also predicted reduced pathological complete response in hormone receptor negative breast cancers [100,110]. However, in a different report, nuclear GLI1 correlates with triple negative breast cancer, and does not predict worse patient survival in ER positive cancer [100]. An association between stromal Gli1 expression and poorer patient outcome has also been reported: high hedgehog ligand expression in breast tumors present with nuclear GLI1 in the adjacent stroma predicted for invasive breast cancers with worse patient outcomes higher grade tumors [108].…”