The hedgehog pathway in triple-negative breast cancer.

Joyce G Habib,Joyce A O'Shaughnessy

doi:10.1002/cam4.833

Joyce G Habib, Joyce A O'Shaughnessy

Open Access

https://doi.org/10.1002/cam4.833

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Journal: Cancer medicine	Publication Date: Aug 18, 2016
Citations: 99	License type: CC BY 4.0

Affiliation: Texas Oncology

Abstract

Treatment of triple‐negative breast cancer (TNBC) remains challenging due to the underlying heterogeneity of this disease coupled with the lack of predictive biomarkers and effective targeted therapies. Intratumoral heterogeneity, particularly enrichment for breast cancer stem cell‐like subpopulations, has emerged as a leading hypothesis for systemic therapy resistance and clinically aggressive course of poor prognosis TNBC. A growing body of literature supports the role of the stem cell renewal Hedgehog (Hh) pathway in breast cancer. Emerging preclinical data also implicate Hh signaling in TNBC pathogenesis. Herein, we review the evidence for a pathophysiologic role of Hh signaling in TNBC and explore mechanisms of crosstalk between the Hh pathway and other key signaling networks as well as their potential implications for Hh‐targeted interventions in TNBC.

Highlights

Triple-negative breast cancer (TNBC), defined immunohistologically by the absence of estrogen (ER), progesterone (PR), and HER2 receptors, is a heterogeneous entity comprising subtypes with distinct clinical and molecular features [1,2,3,4]
In the absence of clinical data, collective findings of preclinical studies are supportive of resistance to SMO antagonists in TNBC and suggest that effective Hh pathway inhibition will necessitate the use of a glioma-associated oncogene (GLI)-targeted approach [42, 43, 54, 55, 90]
We have discussed the current evidence and recent studies highlighting the role of the Hh pathway in the pathogenesis of TNBC and explored mechanisms of deregulated Hh signaling in this breast cancer subtype

Summary

Introduction

Triple-negative breast cancer (TNBC), defined immunohistologically by the absence of estrogen (ER), progesterone (PR), and HER2 receptors, is a heterogeneous entity comprising subtypes with distinct clinical and molecular features [1,2,3,4]. In vitro resistance to doxorubicin, paclitaxel, and cisplatin was shown to be mediated by GLI1 and was associated in TNBC cells with upregulation of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), both transcriptional targets of Hh signaling ([55] Supplemental data).

Results

Conclusion