Metastasis suppressor 1 (MTSS1) demonstrates prognostic value and anti-metastatic properties in breast cancer☆
Introduction
The most deadly aspect of cancer is its ability to metastasise from the primary tumour to secondary sites. The metastatic cascade consists of a series of sequential, interrelated steps that are not as yet completely understood. However, it is known that these metastatic events are modulated by many factors, including metastasis activators and suppressors. Metastasis suppressors, by definition, inhibit metastasis at any step of the metastatic cascade without blocking tumourigenicity.1
Metastasis suppressor 1 (MTSS1), also known as MIM or MIM-B (missing-in-metastasis) was originally identified as a potential metastasis suppressor gene that was present in non-metastatic bladder cancer cell lines, but was not expressed in a metastatic bladder cancer cell line.2 This first study suggested that MIM could be a potential metastasis suppressor. It was also demonstrated that MIM-B induced actin-rich protrusions resembling microspikes and lamellipodia at the plasma membrane and promoted disassembly of actin stress fibres.3 Actin filament assembly is associated with cytoskeletal structure organisation and many forms of cell motility.4 This alteration in actin dynamics will have serious consequences on the metastatic ability of cancer cells.5, 6 This may help explain the involvement of MTSS1 in the metastasis of cancer cells. However, further evidence is required to substantiate this preliminary claim and to elucidate any potential role of MTSS1 in the regulation of tumour cell behaviour.
To date, there are contrasting views to whether or not MTSS1 is in fact a metastasis suppressor. MTSS1 has been reported to play a role as a metastasis suppressor in both prostate cancer7, 8 and bladder cancer2, 8, 9; however, some reports suggest that MTSS1 is unlikely to be metastasis suppressor and instead acts as a scaffold protein that interacts with actin-associated proteins to modulate lamellipodia formation.10 Recently, evidence suggests that MTSS1 is a regulator of carcinogenesis in hepatocellular carcinoma,11 and is a member of the sonic hedgehog (SHH) signalling pathway that modulates Gli responses during growth and carcinogenesis.12, 13
Therefore, a role for MTSS1 in tumourigenesis and metastasis is yet to be established. All these controversial data are due in part to the fact that the study of MTSS1 has been restricted to a limited of cancer types, with little support from the clinical aspect. Studies suggest that further analysis of MTSS1 expression or inactivation in tissue samples and its association with different human malignancies will define a novel candidate to be used as a marker of primary tumours or metastasis.8
In an attempt to clarify the situation, we sought to determine the relevance of MTSS1 in breast cancer. Here, we provide new insights into the biological functions of MTSS1 and its role in breast cancer. In the present study, we examined MTSS1 expression a cohort of human breast cancer patient specimens and demonstrated an inverse correlation between MTSS1 and patient prognosis and survival. Importantly, we further analysed MTSS1 through a series of expression and inactivation studies to clarify MTSS1 function in breast cancer cells.
Section snippets
Cell lines and culture
All cell lines used in this study were obtained from the European Collection for Animal Cell Culture (ECACC, Porton Down, Salisbury, UK), unless otherwise stated. Cells were routinely cultured with Dulbecco’s modified Eagle medium (DMEM) supplemented with 10% foetal calf serum, penicillin and streptomycin (Gibco BRC, Paisley, Scotland).
This study used human breast cancer cells (MDA-MB-157, MDA-MB-231, MDA-MB-435s, MDA-MB-436, MDA-MB-453, MCF-7, BT474, BT549 and ZR-751), human colorectal cancer
MTSS1 mRNA expression in human cell lines
A variety of 21 human normal and cancer cell lines were examined for the presence of MTSS1 through RT-PCR (Fig. 1A) and Quantitative-PCR (Fig. 1B). Of the nine human breast cancer cells examined, MTSS1 was most strongly expressed in the BT474 and MCF-7 cell lines, which are known for having low-invasive potential.20 The MDA-MB-157, MDA-MB-231, MDA-MB-435s, MDA-MB-436 and ZR-751 breast cancer cell lines were negative for MTSS1 transcript. The HRT-18 colon cancer cell line and the PLC/PRF/5 liver
Discussion
Although metastasis suppressor 1 (MTSS1) is suggested to be an exciting new metastasis suppressor; there is little information available on this factor. The knowledge on MTSS1 is particularly weak from a clinical aspect. Supported by a series of cellular function tests, the present study indicates for the first time that MTSS1 acts as a powerful inhibitor to the aggressiveness of breast cancer cells and has strong prognostic and survival relevance in patients with breast cancer.
Our initial
Conflict of interest statement
None declared.
Acknowledgements
We wish to thank Cancer Research Wales and the Albert Hung Foundation for funding this research, Dr. Anthony Douglas-Jones for his expert evaluation of histology slides, and Mr. Gareth Watkins for his technical assistance.
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Grant Support: Cancer Research Wales.