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The Hedgehog signalling pathway in breast development, carcinogenesis and cancer therapy.

Hui M, Cazet A, Nair R, Watkins DN, O'Toole SA, Swarbrick A - Breast Cancer Res. (2013)

Bottom Line: Aberrant activation of the Hedgehog (Hh) signalling pathway has been unambiguously tied to cancer development and progression in a variety of solid malignancies, and the recent approval of vismodegib, an orally bioavailable small-molecule inhibitor of Smoothened, validates Hh signalling as a valuable therapeutic target.Interestingly, Hh ligand overexpression is associated with the BLBC phenotype and a poor outcome in terms of metastasis and breast cancer-related death.In this review, we provide a comprehensive overview of the canonical Hh signalling pathway in mammals, highlight its roles in mammary gland development and breast carcinogenesis and discuss its potential therapeutic value in BLBC.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
Despite the progress achieved in breast cancer screening and therapeutic innovations, the basal-like subtype of breast cancer (BLBC) still represents a particular clinical challenge. In order to make an impact on survival in this type of aggressive breast cancer, new targeted therapeutic agents are urgently needed. Aberrant activation of the Hedgehog (Hh) signalling pathway has been unambiguously tied to cancer development and progression in a variety of solid malignancies, and the recent approval of vismodegib, an orally bioavailable small-molecule inhibitor of Smoothened, validates Hh signalling as a valuable therapeutic target. A number of recent publications have highlighted a role for Hh signalling in breast cancer models and clinical specimens. Interestingly, Hh ligand overexpression is associated with the BLBC phenotype and a poor outcome in terms of metastasis and breast cancer-related death. In this review, we provide a comprehensive overview of the canonical Hh signalling pathway in mammals, highlight its roles in mammary gland development and breast carcinogenesis and discuss its potential therapeutic value in BLBC.

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Small-molecule Hedgehog pathway inhibitors and effects on the Hedgehog signalling pathway. Currently, all of the small-molecule Hedgehog (Hh) pathway therapeutics in clinical trial target Smoothened (SMO). Several compounds targeting the Hh pathway either upstream or downstream of SMO are under development and could be an alternative strategy to overcome acquired resistance to Smo-targeting therapies. GLI, Glioma-associated oncoprotein;HHIP, Hh-interacting protein; PTCH, Patched.
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Figure 3: Small-molecule Hedgehog pathway inhibitors and effects on the Hedgehog signalling pathway. Currently, all of the small-molecule Hedgehog (Hh) pathway therapeutics in clinical trial target Smoothened (SMO). Several compounds targeting the Hh pathway either upstream or downstream of SMO are under development and could be an alternative strategy to overcome acquired resistance to Smo-targeting therapies. GLI, Glioma-associated oncoprotein;HHIP, Hh-interacting protein; PTCH, Patched.

Mentions: The first naturally occurring Hh inhibitor identified was termed cyclopamine. Isolated from the wild corn lily Veratrum californicum, this steroidal alkaloid was discovered through investigations of one-eyed, or cyclopic, lambs whose mothers grazed on corn lily [85] (Table 1; Figure 3). Cyclopamine was the first to be shown to inhibit Hh signalling by binding SMO but did not represent a suitable therapeutic agent due to its poor bioavailability, short half-life, non-specific toxicity and chemical instability [86]. Several Hh inhibitors have been subsequently identified via large-scale chemical library screening approaches. In general, these compounds can be classified as specific inhibitors of Hh ligand, SMO or GLI transcription factors [5].


The Hedgehog signalling pathway in breast development, carcinogenesis and cancer therapy.

Hui M, Cazet A, Nair R, Watkins DN, O'Toole SA, Swarbrick A - Breast Cancer Res. (2013)

Small-molecule Hedgehog pathway inhibitors and effects on the Hedgehog signalling pathway. Currently, all of the small-molecule Hedgehog (Hh) pathway therapeutics in clinical trial target Smoothened (SMO). Several compounds targeting the Hh pathway either upstream or downstream of SMO are under development and could be an alternative strategy to overcome acquired resistance to Smo-targeting therapies. GLI, Glioma-associated oncoprotein;HHIP, Hh-interacting protein; PTCH, Patched.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672663&req=5

Figure 3: Small-molecule Hedgehog pathway inhibitors and effects on the Hedgehog signalling pathway. Currently, all of the small-molecule Hedgehog (Hh) pathway therapeutics in clinical trial target Smoothened (SMO). Several compounds targeting the Hh pathway either upstream or downstream of SMO are under development and could be an alternative strategy to overcome acquired resistance to Smo-targeting therapies. GLI, Glioma-associated oncoprotein;HHIP, Hh-interacting protein; PTCH, Patched.
Mentions: The first naturally occurring Hh inhibitor identified was termed cyclopamine. Isolated from the wild corn lily Veratrum californicum, this steroidal alkaloid was discovered through investigations of one-eyed, or cyclopic, lambs whose mothers grazed on corn lily [85] (Table 1; Figure 3). Cyclopamine was the first to be shown to inhibit Hh signalling by binding SMO but did not represent a suitable therapeutic agent due to its poor bioavailability, short half-life, non-specific toxicity and chemical instability [86]. Several Hh inhibitors have been subsequently identified via large-scale chemical library screening approaches. In general, these compounds can be classified as specific inhibitors of Hh ligand, SMO or GLI transcription factors [5].

Bottom Line: Aberrant activation of the Hedgehog (Hh) signalling pathway has been unambiguously tied to cancer development and progression in a variety of solid malignancies, and the recent approval of vismodegib, an orally bioavailable small-molecule inhibitor of Smoothened, validates Hh signalling as a valuable therapeutic target.Interestingly, Hh ligand overexpression is associated with the BLBC phenotype and a poor outcome in terms of metastasis and breast cancer-related death.In this review, we provide a comprehensive overview of the canonical Hh signalling pathway in mammals, highlight its roles in mammary gland development and breast carcinogenesis and discuss its potential therapeutic value in BLBC.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
Despite the progress achieved in breast cancer screening and therapeutic innovations, the basal-like subtype of breast cancer (BLBC) still represents a particular clinical challenge. In order to make an impact on survival in this type of aggressive breast cancer, new targeted therapeutic agents are urgently needed. Aberrant activation of the Hedgehog (Hh) signalling pathway has been unambiguously tied to cancer development and progression in a variety of solid malignancies, and the recent approval of vismodegib, an orally bioavailable small-molecule inhibitor of Smoothened, validates Hh signalling as a valuable therapeutic target. A number of recent publications have highlighted a role for Hh signalling in breast cancer models and clinical specimens. Interestingly, Hh ligand overexpression is associated with the BLBC phenotype and a poor outcome in terms of metastasis and breast cancer-related death. In this review, we provide a comprehensive overview of the canonical Hh signalling pathway in mammals, highlight its roles in mammary gland development and breast carcinogenesis and discuss its potential therapeutic value in BLBC.

Show MeSH
Related in: MedlinePlus