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28.09.2016 | Ausgabe 3-4/2016 Open Access

Journal of Mammary Gland Biology and Neoplasia 3-4/2016

Patient-derived Mammosphere and Xenograft Tumour Initiation Correlates with Progression to Metastasis

Journal of Mammary Gland Biology and Neoplasia > Ausgabe 3-4/2016
Rachel Eyre, Denis G. Alférez, Kath Spence, Mohamed Kamal, Frances L. Shaw, Bruno M. Simões, Angélica Santiago-Gómez, Aida Sarmiento-Castro, Maria Bramley, Mohammed Absar, Zahida Saad, Sumohan Chatterjee, Cliona Kirwan, Ashu Gandhi, Anne C. Armstrong, Andrew M. Wardley, Ciara S. O’Brien, Gillian Farnie, Sacha J. Howell, Robert B. Clarke
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s10911-016-9361-8) contains supplementary material, which is available to authorized users.
The original version of this article was revised: Table 1 contained the following errors: "Grade" was incorrectly labelled as "Grade 1", “Nodal Involvement” was incorrectly labelled as “Hormone Receptor Status”, the ER positive and ER negative labels were reversed, the Her2 positive was labelled as "Po" instead of "Pos", and "Endocrine therapy" was labelled as" "Endoctrine therapy". In Table 2, "Grade" was incorrectly labelled as "Grade 1", and “Hormone Receptor Status” was incorrectly labelled as “Nodal Involvement”. In Table 3, "Pathology" was incorrectly labelled as “Pathlofy”.
Rachel Eyre and Denis G. Alférez contributed equally to this work.
An erratum to this article is available at http://​dx.​doi.​org/​10.​1007/​s10911-016-9364-5.


Breast cancer specific mortality results from tumour cell dissemination and metastatic colonisation. Identification of the cells and processes responsible for metastasis will enable better prevention and control of metastatic disease, thus reducing relapse and mortality. To better understand these processes, we prospectively collected 307 patient-derived breast cancer samples (n = 195 early breast cancers (EBC) and n = 112 metastatic samples (MBC)). We assessed colony-forming activity in vitro by growing isolated cells in both primary (formation) and secondary (self-renewal) mammosphere culture, and tumour initiating activity in vivo through subcutaneous transplantation of fragments or cells into mice. Metastatic samples formed primary mammosphere colonies significantly more frequently than early breast cancers and had significantly higher primary mammosphere colony formation efficiency (0.9 % vs. 0.6 %; p < 0.0001). Tumour initiation in vivo was significantly higher in metastatic than early breast cancer samples (63 % vs. 38 %, p = 0.04). Of 144 breast cancer samples implanted in vivo, we established 20 stable patient-derived xenograft (PDX) models at passage 2 or greater. Lung metastases were detected in mice from 14 PDX models. Mammosphere colony formation in vitro significantly correlated with the ability of a tumour to metastasise to the lungs in vivo (p = 0.05), but not with subcutaneous tumour initiation. In summary, the breast cancer stem cell activities of colony formation and tumour initiation are increased in metastatic compared to early samples, and predict metastasis in vivo. These results suggest that breast stem cell activity will predict for poor outcome tumours, and therapy targeting this activity will improve outcomes for patients with metastatic disease.

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Supplementary Table 1 Summary of PDX models which spontaneously metastasise to the lung. 14 PDX models demonstrated spontaneous lung metastases (8 EBC, 6 MBC). The number of mice assessed for metastases and the number of mice where metastases were present is shown. NA; information not available (PPTX 107 kb)
Supplementary Fig 1 Sample processing of patient-derived samples. Early breast cancers were removed at surgery and metastatic breast cancers were collected by percutaneous pleural effusion and ascitic fluid aspiration (a). Patients were either consented as “basic consent” or “animal consent”. Samples with basic consent were processed to give a single cell suspension and plated into the low adherence mammosphere assay. Mammospheres over ≥50 μm were counted at 7 days post plating (b). Samples with animal consent were additionally implanted into NSG mice, either as whole fragments (early breast cancers) or cell suspensions (metastatic breast cancers), and monitored for growth over 200 days. Mice where samples reached 1.3cm3 were culled and tumours were implanted into further generations of mice (c) (PPTX 487 kb)
Supplementary Fig 2 Mammosphere formation related to clinical parameters and in vivo tumour initiation. The relationship between mammosphere formation and clinical parameters was assessed in early and metastatic breast cancers. The oestrogen receptor (ER) status of the primary tumour did not predict mammosphere formation in early breast cancers (a), however in patients with metastatic disease those with ER negative tumours formed more mammospheres than patients with ER positive disease (p=0.0187) (b). Mammosphere formation was unrelated to molecular subtype (c, d) or grade (e, f) in either early or metastatic breast cancer, and was unrelated to Nottingham Prognostic index in early breast cancer (g). Mammosphere formation did not predict tumour growth in vivo in early breast cancers (h). Quick score positive for ER = >4. Nottingham prognostic index cut off poor ≥3.4. Data are represented as mean ± SEM. *p<0.05. (PPTX 159 kb)
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