LKB1 Inhibits Breast Cancer Partially through Repressing the Hedgehog Signaling Pathway

Abstract

Constitutive activation of the Hedgehog (Hh) signaling pathway has been implicated in the development of many human malignancies. Hh targets, such as Patched (PTCH), smoothened (SMO), Sonic hedgehog (SHH) and glioma-associated oncogene homologue 1 (GLI1), are markers of Hh signaling activation and expressed in most Hh-associated tumors. The protein kinase LKB1 has been shown to slow proliferation and induce cell-cycle arrest in many cell lines. In this study, we observed that activated LKB1 decreased the expression of factors related to Hh reporter activity in MDA-MB-231 breast cancer cells, including of SMO, SHH and GLI1. In contrast, LKB1 siRNA increased the expression of these target genes. The same results were shown to inhibit the Hh factors Sufu and Hip. Furthermore, we also observed negative correlation between LKB1 and glioma-associated oncogene homologue 1 (GLI1) in three breast cancer cell lines. Meanwhile, LKB1 siRNA rescued the inhibition of cell growth by 3-Keto-N-(aminoethyl-N'-aminocaproyldihydrocinnamoyl) cyclopamine (KAAD-cyclopamine), an antagonist of the Hh element SMO, which suggests that LKB1 acts as the downstream of SMO. In vivo, LKB1 siRNA increased tumor growth in the mammary fat pad, and the expression levels of Hh displayed similar results in vitro. Overexpression of the LKB1 protein in human breast cancers is associated with the expression of Hh. We found that breast carcinomas with detectable Hh had weak or undetectable expression of LKB1, whereas tumors that expressed high levels of LKB1 had undetectable Hh signaling. In this study, we find that LKB1 are negatively correlated with the expression of Hh related transcription factors. These findings suggest that LKB1 may inhibit tumorigenesis by regulating Hh signaling in certain cancers.

Gli1 expression in pancreatic ductal adenocarcinoma and its clinical significance

“…Our results are similar to those from glioma, mammary cancer and SCCHN patients who displayed high expression level of Gli1 and poor prognosis (Zhuang et al, 2013;Xin et al, 2014).…”

Loss of the Polarity Protein PAR3 Activates STAT3 Signaling via an Atypical Protein Kinase C (aPKC)/NF-κB/Interleukin-6 (IL-6) Axis in Mouse Mammary Cells

“…Although many of the signaling pathways involved in breast tumors have been elucidated, others are still being discovered. After many years of speculation that polarity disruption is fundamental to cancer, recent data have confirmed that defects in the epithelial polarity machinery accelerate solid tumor progression in mammals (2)(3)(4)(5)(6). The mechanisms by which polarity restrains tumor progression remain largely unknown.…”

Downregulation of microRNAs 145-3p and 145-5p Is a Long-term Predictor of Postmenopausal Breast Cancer Risk: The ORDET Prospective Study

“…It is worth noting that most of the pathways identified by the clusters of differentially expressed miRNAs were related to both breast cancer and more general cancer development (e.g., ErbB, mTOR, TGFb, Hedgehog, and Wnt pathways; refs. [26][27][28][29][30]. We then observed that the three miRNA clusters targeted pathways also related to metabolic and endocrine systems, such as cholesterol synthesis, steroid biosynthesis, and the insulin pathway recognized in the ORDET cohort, as well as in other studies as pathways involved in breast cancer development (27,31,32).…”