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Establishment and characterisation of a new breast cancer xenograft obtained from a woman carrying a germline BRCA2 mutation.

de Plater L, Laugé A, Guyader C, Poupon MF, Assayag F, de Cremoux P, Vincent-Salomon A, Stoppa-Lyonnet D, Sigal-Zafrani B, Fontaine JJ, Brough R, Lord CJ, Ashworth A, Cottu P, Decaudin D, Marangoni E - Br. J. Cancer (2010)

Bottom Line: The BRCA2 gene is responsible for a high number of hereditary breast and ovarian cancers, and studies of the BRCA2 biological functions are limited by the lack of models that resemble the patient's tumour features.The biological and genetic profiles of the xenograft were compared with that of the patient's tumour using histology, immunohistochemistry (IHC), BRCA2 sequencing, comparative genomic hybridisation (CGH), and qRT-PCR.Histological profile identified the tumour as a basal-like triple-negative breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Preclinical Investigation Unit, Institut Curie - Translational Research Department, Hôpital St Louis, Quadrilatère historique, Porte 13, 1, Ave Claude Vellefaux, Paris 75010, France.

ABSTRACT

Background: The BRCA2 gene is responsible for a high number of hereditary breast and ovarian cancers, and studies of the BRCA2 biological functions are limited by the lack of models that resemble the patient's tumour features. The aim of this study was to establish and characterise a new human breast carcinoma xenograft obtained from a woman carrying a germline BRCA2 mutation.

Methods: A transplantable xenograft was obtained by grafting a breast cancer sample into nude mice. The biological and genetic profiles of the xenograft were compared with that of the patient's tumour using histology, immunohistochemistry (IHC), BRCA2 sequencing, comparative genomic hybridisation (CGH), and qRT-PCR. Tumour response to standard chemotherapies was evaluated.

Results: Histological profile identified the tumour as a basal-like triple-negative breast cancer. Targeted BRCA2 DNA sequencing of the xenograft showed the presence of the mutation previously identified in the carrier. Comparative genomic hybridisation array profiles of the primary tumour and the xenograft revealed a high number of similar genetic alterations. The therapeutic assessment of the xenograft showed sensitivity to anthracyclin-based chemotherapy and resistance to docetaxel. The xenograft was also highly sensitive to radiotherapy and cisplatin-based treatments.

Conclusions: This study describes a new human breast cancer xenograft obtained from a BRCA2-mutated patient. This xenograft provides a new model for the pre-clinical drug development and for the exploration of the drug response biological basis.

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Related in: MedlinePlus

Representative haematoxylin-and-eosin-stained sections of patients and xenografts tumours. Haematoxylin and eosin sections Gx100 (A and B), KI67 (C and D), and CK14 (E and F). Lung metastases are shown in pictures G and H (arrows) clusters of tumour cells obstruct the lumen of a small number of pulmonary arterioles (cancerous emboli), without evident effraction of the arteriolar media.
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fig1: Representative haematoxylin-and-eosin-stained sections of patients and xenografts tumours. Haematoxylin and eosin sections Gx100 (A and B), KI67 (C and D), and CK14 (E and F). Lung metastases are shown in pictures G and H (arrows) clusters of tumour cells obstruct the lumen of a small number of pulmonary arterioles (cancerous emboli), without evident effraction of the arteriolar media.

Mentions: Histopathological analysis was performed with the primary tumour and the xenograft HBCx-17 at passage 6. As shown in Figure 1A and B, the histology of the original tumour was conserved in the xenograft. Indeed, HBCx-17 showed an infiltrating ductal carcinoma with typical loss of tubule formation, prominent nuclear pleomorphism, and mitotic activity. Irregular infiltration of stroma was observed in both patient and xenografts. Assessment of tumour proliferation using Ki67 staining showed a high proliferative rate in the primary tumour, which was increased in the xenograft (Figure 1C and D). Both primary and xenograft tumours were negative for CK5 and CK6 (data not shown) but positive for CK14 expression as shown in Figure 1E and F. Both tumour sample and HBCx-17 are negative for ERBB2 and oestrogen, and progesteron receptor, and the clinical sample presented a strong EGFR staining that the xenograft did not (data not shown).


Establishment and characterisation of a new breast cancer xenograft obtained from a woman carrying a germline BRCA2 mutation.

de Plater L, Laugé A, Guyader C, Poupon MF, Assayag F, de Cremoux P, Vincent-Salomon A, Stoppa-Lyonnet D, Sigal-Zafrani B, Fontaine JJ, Brough R, Lord CJ, Ashworth A, Cottu P, Decaudin D, Marangoni E - Br. J. Cancer (2010)

Representative haematoxylin-and-eosin-stained sections of patients and xenografts tumours. Haematoxylin and eosin sections Gx100 (A and B), KI67 (C and D), and CK14 (E and F). Lung metastases are shown in pictures G and H (arrows) clusters of tumour cells obstruct the lumen of a small number of pulmonary arterioles (cancerous emboli), without evident effraction of the arteriolar media.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2967069&req=5

fig1: Representative haematoxylin-and-eosin-stained sections of patients and xenografts tumours. Haematoxylin and eosin sections Gx100 (A and B), KI67 (C and D), and CK14 (E and F). Lung metastases are shown in pictures G and H (arrows) clusters of tumour cells obstruct the lumen of a small number of pulmonary arterioles (cancerous emboli), without evident effraction of the arteriolar media.
Mentions: Histopathological analysis was performed with the primary tumour and the xenograft HBCx-17 at passage 6. As shown in Figure 1A and B, the histology of the original tumour was conserved in the xenograft. Indeed, HBCx-17 showed an infiltrating ductal carcinoma with typical loss of tubule formation, prominent nuclear pleomorphism, and mitotic activity. Irregular infiltration of stroma was observed in both patient and xenografts. Assessment of tumour proliferation using Ki67 staining showed a high proliferative rate in the primary tumour, which was increased in the xenograft (Figure 1C and D). Both primary and xenograft tumours were negative for CK5 and CK6 (data not shown) but positive for CK14 expression as shown in Figure 1E and F. Both tumour sample and HBCx-17 are negative for ERBB2 and oestrogen, and progesteron receptor, and the clinical sample presented a strong EGFR staining that the xenograft did not (data not shown).

Bottom Line: The BRCA2 gene is responsible for a high number of hereditary breast and ovarian cancers, and studies of the BRCA2 biological functions are limited by the lack of models that resemble the patient's tumour features.The biological and genetic profiles of the xenograft were compared with that of the patient's tumour using histology, immunohistochemistry (IHC), BRCA2 sequencing, comparative genomic hybridisation (CGH), and qRT-PCR.Histological profile identified the tumour as a basal-like triple-negative breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Preclinical Investigation Unit, Institut Curie - Translational Research Department, Hôpital St Louis, Quadrilatère historique, Porte 13, 1, Ave Claude Vellefaux, Paris 75010, France.

ABSTRACT

Background: The BRCA2 gene is responsible for a high number of hereditary breast and ovarian cancers, and studies of the BRCA2 biological functions are limited by the lack of models that resemble the patient's tumour features. The aim of this study was to establish and characterise a new human breast carcinoma xenograft obtained from a woman carrying a germline BRCA2 mutation.

Methods: A transplantable xenograft was obtained by grafting a breast cancer sample into nude mice. The biological and genetic profiles of the xenograft were compared with that of the patient's tumour using histology, immunohistochemistry (IHC), BRCA2 sequencing, comparative genomic hybridisation (CGH), and qRT-PCR. Tumour response to standard chemotherapies was evaluated.

Results: Histological profile identified the tumour as a basal-like triple-negative breast cancer. Targeted BRCA2 DNA sequencing of the xenograft showed the presence of the mutation previously identified in the carrier. Comparative genomic hybridisation array profiles of the primary tumour and the xenograft revealed a high number of similar genetic alterations. The therapeutic assessment of the xenograft showed sensitivity to anthracyclin-based chemotherapy and resistance to docetaxel. The xenograft was also highly sensitive to radiotherapy and cisplatin-based treatments.

Conclusions: This study describes a new human breast cancer xenograft obtained from a BRCA2-mutated patient. This xenograft provides a new model for the pre-clinical drug development and for the exploration of the drug response biological basis.

Show MeSH
Related in: MedlinePlus