The Hedgehog Signaling Pathway: A Viable Target in Breast Cancer?

Abstract

The hedgehog (Hh) pathway plays a key role in embryonic development and stem cell programs. Deregulation of the Hh pathway is a key driver of basal cell carcinoma, and therapeutic targeting led to approval of Hh inhibitor, vismodegib, in the management of this cancer. The Hh pathway is implicated in other malignancies including hormone receptor (HR+) positive and triple negative breast cancer (TNBC). Hh signaling, which is activated in human mammary stem cells, results in activation of glioma-associated oncogene (GLI) transcription factors. High GLI1 expression correlates with worse outcomes in breast cancer. Non-canonical GLI1 activation is one mechanism by which estrogen exposure promotes breast cancer stem cell proliferation and epithelial–mesenchymal transition. Tamoxifen resistant cell lines show aberrant activation of Hh signaling, and knockdown of Hh pathway inhibited growth of tamoxifen resistant cells. As in other cancers Hh signaling is activated by the PI3K/AKT pathway in these endocrine resistant cell lines. Hh pathway activation has also been reported to mediate chemotherapy resistance in TNBC via various mechanisms including paracrine signaling to tumor micro-environment and selective proliferation of cancer stem cells. Co-activation of Hh and Wnt signaling pathways is a poor prognostic marker in TNBC. Early phase clinical trials are evaluating the combination of smoothened (SMO) inhibitors and chemotherapy in TNBC. In addition to SMO inhibitors like vismodegib and sonidegib, which are in clinical use for basal cell carcinoma, GLI1 inhibitors like GANT58 and GANT61 are in preclinical drug development and might be an effective mechanism to overcome drug resistance in breast cancer. Gene signatures predictive of Hh pathway activation could enrich for patients likely to respond to these agents.

Cellular Plasticity in Breast Cancer Progression and Therapy

“…The Hh pathway is involved in embryonic mammary gland induction, development of ductal architecture and the differentiation that occurs prior to lactation (Lewis and Veltmaat, 2004). Emerging evidence suggests that dysregulation of Hh signaling is implicated in breast cancer development (Hatsell and Frost, 2007;Bhateja et al, 2019), though there is controversy around whether the primary role is in the tumor cells themselves or in the tumor microenvironment Sims-Mourtada et al, 2015;Yang et al, 2016;Koike et al, 2017;Neelakantan et al, 2017). Multiple studies have linked Hh signaling to promotion and maintenance of CSC phenotypes in breast cancer.…”

“…Compared with other signaling pathways, the strategies targeting the Hh pathway are more diverse. The Hh pathway can be inhibited via blocking Hh ligands, receptors (such as SMO), or downstream transcription factors (GLI) (Bhateja et al, 2019). A monoclonal antibody against Hh ligands (5E1) was shown to inhibit breast cancer growth and metastasis in mouse models (O'Toole et al, 2011).…”

Signal Transduction Pathway Activity in High-Grade, Serous Ovarian Carcinoma Reveals a More Favorable Prognosis in Tumors with Low PI3K and High NF-κB Pathway Activity: A Novel Approach to a Long-Standing Enigma

“…All included samples were taken prior to start of chemotherapy. As chemotherapeutic treatment affects STP activity, the results of our analyses may have been very different in samples taken after chemotherapy [51,52]. As we made use of publicly available databases, we were unable to revise pathology diagnoses.…”

“…Samples were eligible if they were taken prior to start of chemotherapy. Samples taken after start of chemotherapy were excluded, as it is known that the treatment affects STP activity in cancer cells [51,52]. We found two datasets suitable for analysis: GSSE9891, with an accompanying paper by Tothill et al and GSE32062, with an accompanying paper by Yoshihara et al All samples were subject to extensive quality control (QC) based on 12 quality parameters following Affymetrix recommendations and previously published literature [10,56,57].…”

Personalized analysis of breast cancer using sample-specific networks

“…Toll-like receptors may play dual roles in human cancers (Khademalhosseini & Arababadi, 2019). The co-activation of the Hedgehog and Wnt signaling pathways is a poor prognostic marker in TNBC (Bhateja et al, 2019). Prl-3 is closely related to cell migration and invasion in TNBC (Gari et al, 2016).…”