Involvement of hedgehog pathway in early onset, aggressive molecular subtypes and metastatic potential of breast cancer

Riaz, Syeda Kiran, Khan, Jahangir Sarwar, Shah, Syed Tahir Abbas, Wang, Fen, Ye, Lin ORCID: https://orcid.org/0000-0002-0303-2409, Jiang, Wen ORCID: https://orcid.org/0000-0002-3283-1111 and Malik, Muhammad Faraz Arshad 2018. Involvement of hedgehog pathway in early onset, aggressive molecular subtypes and metastatic potential of breast cancer. Cell Communication and Signaling 16 , 3. 10.1186/s12964-017-0213-y

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Abstract

Background Dysregulation of hedgehog pathway is observed in numerous cancers. Relevance of hedgehog pathway genes in cancer cohort and inhibition of its downstream effector (GLI1) towards metastasis in cell lines are explored in the study. Method One hundred fifty fresh tumours of breast cancer patients were collected for the study. Based on differential expression, panel of 6 key regulators of the pathway (SHH, DHH, IHH, PTCH1, SMO and GLI1) in microarray datasets were identified. Expressional profiles of aforementioned genes were later correlated with clinico-pathological parameters in Pakistani breast cancer cohort at transcript and protein levels. In addition, GLI1 over expressing breast cancer cell lines (MDA-MB-231 and MCF-7) were treated with GANT61 to explore its probable effects on metastasis. Result SHH, DHH, PTCH1 and GLI1 were significantly over-expressed in tumours as compared with respective normal mammary tissues. A significant correlation of SHH, DHH and GLI1 expression with advanced tumour size, stages, grades, nodal involvement and distant metastasis was observed (p < 0.05). Over-expression of SHH, DHH and GLI1 was significantly related with patients having early onset and pre-menopausal status. Of note, hedgehog pathway was frequently up regulated in luminal B and triple negative breast cancer affected women. In addition, positive correlations were observed among aforementioned members of pathway and Ki67 (r-value: 0.63–0.78) emphasizing their role towards disease progression. Exposure of GANT61 (inhibitor for GLI1) significantly restricted cell proliferation, reduced cell motility and invasion. Conclusion Role of activated hedgehog pathway in breast cancer metastasis provides a novel target for cancer therapy against aggressive cancer subtypes.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	BioMed Central
ISSN:	1478-811X
Date of First Compliant Deposit:	16 January 2018
Date of Acceptance:	28 December 2017
Last Modified:	19 Nov 2024 20:00
URI:	https://orca.cardiff.ac.uk/id/eprint/108055

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