Targeting matrilysin and its impact on tumor growth in vivo: the potential implications in breast cancer therapy

Jiang, Wen Guo ORCID: https://orcid.org/0000-0002-3283-1111, Davies, Gaynor, Martin, Tracey Amanda ORCID: https://orcid.org/0000-0003-2690-4908, Parr, Christian, Watkins, Gareth, Mason, Malcolm David ORCID: https://orcid.org/0000-0003-1505-2869, Mokbel, Kefah and Mansel, Robert Edward ORCID: https://orcid.org/0000-0002-8051-0726 2005. Targeting matrilysin and its impact on tumor growth in vivo: the potential implications in breast cancer therapy. Clinical Cancer Research 11 (16) , pp. 6012-6019. 10.1158/1078-0432.CCR-05-0275

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Abstract

Introduction: Matrilysin (MMP-7) is a metalloproteinase that is involved in the degradation of extracellular matrix, invasion, and tumor progression. The current study examined if targeting matrilysin using retroviral ribozyme transgenes may have an impact on breast cancer cells and may have clinical implications. Experimental Design: Retroviral hammerhead ribozyme transgenes were designed to specifically target human matrilysin mRNA. The breast cancer cell MDA-MB-231 was transfected with either a retroviral matrilysin transgene or a control retroviral transgene. Stably transfected cells were tested for their invasiveness and migratory properties in vitro. The cells were also used in creating a tumor model in athymic nude mice in which the growth of tumors and levels of matrilysin were assessed. In addition, levels of both protein and mRNA of matrilysin were investigated in a cohort of human breast tumors. Results: Expression of matrilysin in MDA-MB-231 was successfully eliminated by the retroviral hammerhead ribozyme transgene for matrilysin as revealed by reverse transcription-PCR. Matrilysin transgene–transduced cancer cells (MDA-MB-231?Matrilysin) exhibited a significantly lower degree of invasion (number of invading cells 16.0 ± 2.5) compared with wild type (MDA-MB-231WT; 26.2 ± 6.2, P < 0.05) or control transgene-transduced cancer cells (MDA-MB-231pRevTRE; 25.3 ± 4.2, P < 0.01). However, the rate of growth of the cells in vitro was not significantly affected. In the in vivo tumor model, MDA-MB-231?Matrilysin tumors, which had very low levels of immunoreactive matrilysin, grew at a significantly lower rate (0.24 ± 0.03 cm3, 4 weeks after inoculation) compared with the wild-type MDA-MB-231WT (1.46 ± 0.04 cm3) and MDA-MB-231pRevTRE (1.12 ± 1.0 cm3) tumors. In human breast tumors, breast cancer cells stained matrilysin at a significantly higher density, compared with normal mammary epithelium. The highest level of matrilysin was seen in high-grade tumors and that from patients with moderate and poor prognosis. Finally, high levels of matrilysin were significantly linked with a poor long-term survival (P = 0.0143). Conclusion: Matrilysin, which is aberrantly expressed in human breast tumors, can be effectively eliminated from breast cancer cells by way of hammerhead ribozyme transgene. Elimination of matrilysin is associated with low invasiveness and slow tumor growth. Taken together, the study suggests that targeting matrilysin may have important therapeutic implications.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	Matrilysin; invasion; ribozyme; molecular targeting; breast cancer; tumor model
ISSN:	1557-3265
Last Modified:	17 Oct 2022 08:25
URI:	https://orca.cardiff.ac.uk/id/eprint/131

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