Outgrowth of BT-474 human breast cancer cells in immune-deficient mice: a new in vivo model for hormone-dependent breast cancer

Slooten, Henk Jan Van; Bonsing, Bert A.; Hiller, Alan J.; Colbern, Gail; Dierendonck, Jan Hein van; Cornelisse, C.J.; Smith, Helene S.

doi:10.1038/bjc.1995.271

Cited by 42 publications

(23 citation statements)

References 44 publications

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“…tasis when placed in the neck of nude mice (31). Currently, no ErbB2 model of breast cancer has been reported to metastasize after orthotopic transplantation into the mammary fat pad.…”

Section: Erbb2 Induces Expression Of P120 In Mammary Epithelialmentioning

confidence: 99%

HER2/ErbB2-induced Breast Cancer Cell Migration and Invasion Require p120 Catenin Activation of Rac1 and Cdc42

Johnson¹,

Seachrist²,

DeLeon-Rodriguez³

et al. 2010

Journal of Biological Chemistry

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Breast cancers that overexpress the receptor tyrosine kinase ErbB2/HER2/Neu result in poor patient outcome because of extensive metastatic progression. Herein, we delineate a molecular mechanism that may govern this malignant phenotype. ErbB2 induction of migration requires activation of the small GTPases Rac1 and Cdc42. The ability of ErbB2 to activate these small GTPases necessitated expression of p120 catenin, which is itself up-regulated by signaling through ErbB2 and the tyrosine kinase Src. Silencing p120 in ErbB2-dependent breast cancer cell lines dramatically inhibited migration and invasion as well as activation of Rac1 and Cdc42. In contrast, overexpression of constitutively active mutants of these GTPases reversed the effects of p120 silencing. Lastly, ectopic expression of p120 promoted migration and invasion and potentiated metastatic progression of a weakly metastatic, ErbB2-dependent breast cancer cell line. These results suggest that p120 acts as an obligate intermediate between ErbB2 and Rac1/Cdc42 to modulate the metastatic potential of breast cancer cells.HER2/Neu/ErbB2 (epidermal growth factor receptor 2) is a member of the epidermal growth factor receptor (EGFR) 2 family that is amplified and overexpressed in 20 -30% of breast cancers. HER2/ErbB2-positive breast cancer yields a poor patient prognosis because of a high incidence of metastases and intrinsic resistance to endocrine and conventional chemotherapy (1). ErbB2 is the preferred heterodimerization partner for EGFR, ErbB3, and ErbB4 (2). The large range of downstream signaling targets induced by ErbB2-containing heterodimers permits this receptor and its partners to modulate a wide array of cellular processes. Of these, the nonreceptor tyrosine kinase Src, PI3K, and MAPK pathways are the most studied in mediating ErbB2 responsiveness, which includes increased proliferation, survival, motility, and invasion (3).ErbB2-induced cell migration and invasion, and hence metastatic potential, requires activation of Src and its downstream signaling pathways (4). Src also positively provides feedback and stabilizes competent ErbB2/ErbB3 heterocomplexes to enhance PI3K/Akt signaling (5). ErbB2 overexpression in MDA-MB-435 cells enhances formation of metastases by increasing Src synthesis and decreasing its degradation by calpain (6). Similarly, signaling from ErbB2 to Akt is necessary to promote metastatic potential because attenuation of the Akt pathway by pharmacological inhibitors or RNAi decreases the formation of metastases by the ErbB2-dependent 21T breast cancer cell line (7).

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“…tasis when placed in the neck of nude mice (31). Currently, no ErbB2 model of breast cancer has been reported to metastasize after orthotopic transplantation into the mammary fat pad.…”

Section: Erbb2 Induces Expression Of P120 In Mammary Epithelialmentioning

confidence: 99%

HER2/ErbB2-induced Breast Cancer Cell Migration and Invasion Require p120 Catenin Activation of Rac1 and Cdc42

Johnson¹,

Seachrist²,

DeLeon-Rodriguez³

et al. 2010

Journal of Biological Chemistry

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“…Following injection, the mice were monitored for the formation of a primary tumor at the injection site. The largest diameter (L) and smallest diameter (S) of each tumor were measured weekly with calipers, and tumor volumes calculated (Volume=L6S 2 60.52) (Van Slooten et al, 1995). Five weeks after injection the mice were sacri®ced and examined.…”

Section: In Vivo Studiesmentioning

confidence: 99%

Consequences of altered TGF-β expression and responsiveness in breast cancer: evidence for autocrine and paracrine effects

et al. 2002

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To characterize the impact of increased production of TGF-b in a xenograft model of human breast cancer, TGF-b-responsive MDA-231 cells were genetically modi®ed by stable transfection so as to increase their production of active TGF-b1. Compared with control cells, cells that produced increased amounts of TGF-b proliferated in vitro more slowly. In vivo, however, tumors derived from these cells exhibited increased proliferation and grew at an accelerated pace. To evaluate the role of autocrine TGF-b signaling, cells were also transfected with a dominant-negative truncated type II TGF-b receptor (TbRII). Disruption of autocrine TGF-b signaling in the TGF-b-overexpressing cells reduced their in vivo growth rate. Co-inoculation of Matrigel with the TGF-b-overexpressing cells expressing the truncated TbRII compensated for their diminished in vivo growth capacity, compared with the TGF-b-overexpressing cells with an intact autocrine loop. Tissue invasion by the tumor was a distinctive feature of the TGF-b-overexpressing cells, whether or not the autocrine loop was intact. Furthermore, tumors derived from TGFb-overexpressing cells, irrespective of the status of the autocrine TGF-b-signaling pathway, had a higher incidence of lung metastasis. Consistent with the suggestion that TGF-b's enhancement of invasion and metastasis is paracrine-based, we observed no signi®cant di erences among the cell clones in an in vitro invasion assay. Thus, in this experimental model system in vitro assays of cell proliferation and invasion do not accurately re¯ect in vivo observations, perhaps due to autocrine and paracrine e ects of TGF-b that in¯uence the important in vivo-based phenomena of tumor growth, invasion, and metastasis.

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“…At present, numerous breast carcinoma cell lines established from primary solid human breast carcinoma or from the metastatic pleural fluids are available for various research (Nordquist et al, 1975;Engel and Young, 1978;Langlois et al, 1979;Whitehead et al, 1983;Chu et al, 1985;Mehta et al, 1992;1995b;Watanabe et al, 1992;Slooten et al, 1995); however, only a limited number of these cell lines are tumorigenic in mice, and only two to three of these cell lines show distant metastasis when transplanted s.c. into athymic mice (Shafie and Liotta, 1980;Price et al, 1990;Brunner et al, 1992;Mehta et al, 1993). In addition the incidence of metastasis in these cell lines varies in different laboratories (Shafie and Liotta, 1980).…”

Section: Discussionmentioning

confidence: 99%

Development of a new metastatic human breast carcinoma xenograft line

Mehta

Graves²,

Shilkaitis³

et al. 1998

Br J Cancer

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Summary Xenografts originated from human tumours offer the most appropriate research material for in vivo experimental research. However, primary human breast carcinomas are difficult to grow when transplanted in athymic mice: tumour take is less than 15%. Recently, we have achieved 60% tumour take by injecting tumour cell suspensions mixed with Matrigel. Human breast xenografts originated from primary breast carcinoma also frequently show the potential to metastasize spontaneously. In the present study, we generated a human breast carcinoma xenograft line (UISO-BCA-NMT-18) that shows 100% tumorigenicity and 80-100% lung metastasis when transplanted s.c. in athymic mice. We have studied in detail the characteristics of the xenograft and the patient's tumour from which the xenograft line originated. Both the xenograft and the patient's tumour showed intense staining for mutant p53 nuclear protein, and high expression of U-PA, PAI and u-PAR. In vivo growth of the xenograft is stimulated by exogenous supplementation of oestrogen. This xenograft is continuously growing in mice and has shown 80-100% metastasis for the last three successive in vivo passages. This well-characterized, oestrogenresponsive, metastatic breast carcinoma xenograft line will provide excellent research material for metastasis-related research.Keywords: breast cancer; xenograft; cell line; metastasis Metastasis of primary tumour to the visceral organs is a major cause of cancer-associated mortality. Despite considerable progress in the last decade in the areas of early detection and surgical and chemotherapeutic management of clinically less advanced cancers, treatment of metastatic disease is still a major puzzle for oncologists. Research on metastatic disease has severely suffered from lack of suitable experimental models. Human tumour xenografts established from well-characterized clinical material provide an important research tool for multidisciplinary research. In most cases, xenografts originated in vivo in experimental animals preserve many of the original phenotypic, biological and genotypic characteristics from which they originate (Giovanella et al, 1989;Mehta et al, 1995a). However, human breast carcinomas are difficult to grow in vitro in culture (Nordquist et al, 1975;Engel and Young, 1978;Langlois et al, 1979;Whitehead et al, 1983;Chu et al, 1985;Mehta et al, 1992;1995b ;Watanabe et al, 1992) or in vivo in experimental animals (Sabestany et al, 1979;Shafie and Liotta, 1980;Rae-Venter and Reid, 1980;Giovanella et al, 1985;Price and Zhang, 1990;Hurst J, et al, 1993; Mehta et al, 1993), and they rarely metastasize when transplanted subcutaneously (Shafie and Liotta, 1980;Price et al, 1990; Brunner et al, 1992; Mehta et al, 1993).Recently, we obtained significant success in establishing xenografts from primary breast carcinomas, and many of these xenografts showed potential for spontaneous metastasis in athymic mice when transplanted s.c. (Mehta et al, 1993). Initially, we used Matrigel to develop xenografts from primary breast carci...

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Outgrowth of BT-474 human breast cancer cells in immune-deficient mice: a new in vivo model for hormone-dependent breast cancer

Cited by 42 publications

References 44 publications

HER2/ErbB2-induced Breast Cancer Cell Migration and Invasion Require p120 Catenin Activation of Rac1 and Cdc42

HER2/ErbB2-induced Breast Cancer Cell Migration and Invasion Require p120 Catenin Activation of Rac1 and Cdc42

Consequences of altered TGF-β expression and responsiveness in breast cancer: evidence for autocrine and paracrine effects

Development of a new metastatic human breast carcinoma xenograft line

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