Expression of Gli1 correlates with the transition of breast cancer cells to estrogen-independent growth

Abstract

The failure of breast cancer treatment is largely due to the development of estrogen independence. Current data illustrate that Hedgehog (Hh) signaling may play an important role in breast cancer development. Here, we show that the expression of the Hh effector protein, Gli1 was significantly higher in estrogen-independent breast cancer cells than in estrogen-dependent cells. Our data showed for the first time that stable expression of Gli1 in ER positive breast cancer cell lines MCF-7 and T47D can induce estrogen-independent proliferation and promote G1/S phase transition, which associated with cyclin-Rb axi. Gli1 can also attenuate the response of proliferation to estrogenic stimulation, which was correlated with down-regulation of expression of ERalpha and PR, as well as down-regulation of transactivation of ERalpha. Our results suggest that up-regulation of Gli1 in breast cancer cells may be one of the mechanisms responsible for developing estrogen independence and this process may be regulated through down-regulation of expression and transactivation of ERalpha.

Overexpression of Hedgehog signaling molecules and its involvement in triple-negative breast cancer

“…These findings indicate that, by regulating the continuous activation of breast CSCs, the Hh signaling pathway is involved, not only in progression, but also in invasion and metastasis. In addition, the expression of GLI1 was inversely correlated with ER, consistent with a previous study (32) that revealed that GlI1 expression was decreased in ER-positive breast cancer cell lines MCF-7 and T47D. These data indicate that GLI1 may attenuate the response to estrogenic stimulation by negatively regulating ER signaling, which may be the reason for TNBC patients exhibiting insensitivity to hormone therapy.…”

Estrogen promotes stemness and invasiveness of ER-positive breast cancer cells through Gli1 activation

“…Although 60–70% of human breast cancers are ER-positive [27] and respond to anti-estrogen therapy, many of them will inevitably progress to the estrogen-independent stage and develop resistance to anti-estrogen therapy [14]. The existence of CSCs offers a simple explanation as to the presence of endocrine resistance in breast cancer [28-30].…”

“…Although abundant evidence has suggested that estrogen sustains the growth of breast cancer cells expressing functional estrogen receptors (ERs) [14], the role of estrogen in promoting breast CSCs remains controversial. Some researchers think that ER-positive cells contribute to the stem cell compartment directly stimulated by hormones [15,16], while others consider that estrogen may stimulate the expansion of a specific stem cell compartment in a paracrine manner [17-19].…”

(−)-Epigallocatechin-3-gallate induces apoptosis and suppresses proliferation by inhibiting the human Indian Hedgehog pathway in human chondrosarcoma cells

“…GLI-mediated transcriptional activation results in the up-regulation of target genes including the transmembrane protein PTCH-1 and the transcription factor GLI-1 (Lum and Beachy 2004). It has been reported that over-expression of this pathway is highly associated with tumor development and progression in several types of human cancers including lung (Ruiz i Altaba et al 2002), human glioma (Kinzler et al 1981), biliary (Lauth and Toftgard 2007), and breast cancers (Zhao et al 2010). In addition, high expression of the Hedgehog target genes PTCH-1 and GLI-1 has been reported in chondrosarcoma cells (Tiet et al 2006).…”