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Inflammatory breast cancer (IBC): clues for targeted therapies.

Fernandez SV, Robertson FM, Pei J, Aburto-Chumpitaz L, Mu Z, Chu K, Alpaugh RK, Huang Y, Cao Y, Ye Z, Cai KQ, Boley KM, Klein-Szanto AJ, Devarajan K, Addya S, Cristofanilli M - Breast Cancer Res. Treat. (2013)

Bottom Line: Also, CD44 was amplified in triple-negative IBC cells (10-3 copies).Additionally, FC-IBC02 showed amplification of ALK and NOTCH3.These results indicate that MYC, ATAD2, CD44, NOTCH3, ALK and/or FAK1 may be used as potential targeted therapies against IBC.

View Article: PubMed Central - PubMed

Affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Sandra.Fernandez@jefferson.edu

ABSTRACT
Inflammatory breast cancer (IBC) is the most aggressive type of advanced breast cancer characterized by rapid proliferation, early metastatic development and poor prognosis. Since there are few preclinical models of IBC, there is a general lack of understanding of the complexity of the disease. Recently, we have developed a new model of IBC derived from the pleural effusion of a woman with metastatic secondary IBC. FC-IBC02 cells are triple negative and form clusters (mammospheres) in suspension that are strongly positive for E-cadherin, β-catenin and TSPAN24, all adhesion molecules that play an important role in cell migration and invasion. FC-IBC02 cells expressed stem cell markers and some, but not all of the characteristics of cells undergoing epithelial mesenchymal transition (EMT). Breast tumor FC-IBC02 xenografts developed quickly in SCID mice with the presence of tumor emboli and the development of lymph node and lung metastases. Remarkably, FC-IBC02 cells were able to produce brain metastasis in mice on intracardiac or intraperitoneal injections. Genomic studies of FC-IBC02 and other IBC cell lines showed that IBC cells had important amplification of 8q24 where MYC, ATAD2 and the focal adhesion kinase FAK1 are located. MYC and ATAD2 showed between 2.5 and 7 copies in IBC cells. FAK1, which plays important roles in anoikis resistance and tumor metastasis, showed 6-4 copies in IBC cells. Also, CD44 was amplified in triple-negative IBC cells (10-3 copies). Additionally, FC-IBC02 showed amplification of ALK and NOTCH3. These results indicate that MYC, ATAD2, CD44, NOTCH3, ALK and/or FAK1 may be used as potential targeted therapies against IBC.

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Related in: MedlinePlus

Chromosome 8 in IBC and non-IBC cells. Copy number and loss of heterozygosity (LOH) were studied using Affymetrix CytoScan™ HD arrays. The chromosome 8 in different IBC and non-IBC cells is shown
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Fig4: Chromosome 8 in IBC and non-IBC cells. Copy number and loss of heterozygosity (LOH) were studied using Affymetrix CytoScan™ HD arrays. The chromosome 8 in different IBC and non-IBC cells is shown

Mentions: High-resolution arrays were used to evaluate copy number and LOH in FC-IBC02 cells and other triple-negative (Mary X, SUM149, FC-IBC01) and ErbB2-positive (MDA-IBC3, SUM190, KPL4, KMO-015) IBC cell lines. Also, non-IBC cells (MFC-7, MDA-MB231, MDA-MB468, SUM159) were included in these studies to compare the profiles between IBC and non-IBC cells. FC-IBC02 cells showed complicated genomic alterations in all chromosomes with the exception of chromosome 12 (Suppl. Fig. 2). Gains/amplifications were more common than deletions/losses; FC-IBC02 cells showed scattered genomic profile (deletions) on 11q chromosome arm known as chromothripsis; the copy number profile across this chromosome arm shows many positions at which copy number changes between one or two copies (Suppl. Fig. 2). Copy number and LOH studies were also performed for Mary X (Suppl. Fig. 3), SUM149 (Suppl. Fig. 4) and FC-IBC01 (Suppl. Fig. 5). Most of the IBC cells showed multiple amplifications of 8q having 3–10 copies of this chromosomal arm (Fig. 4). The 8q is the location of the oncogene MYC, MTDH1, PVT1, FAK1 (also known as PTK2K) and ATAD2 between other genes. In contrast, the non-IBC cell lines studied showed only 1–4 copies of 8q (Fig. 4). IBC cells showed 2.5–7 copies of the oncogene MYC and, although MYC was also amplified in non-IBC cells, the number of copies was lower in non-IBC (1–3 copies) with the exception of SUM159 cells that have a focal MYC amplification (Table 1). PTK2/FAK1 also showed more copies in IBC (2.5–7 copies) than in non-IBC cells (1–2.5 copies) (Table 1). Metadherin (MTDH1) showed 2.5–6 copies in IBC and 1–3 copies in non-IBC cell lines; ATAD2 showed 2.5–6 copies in IBC and 1–3.5 copies in non-IBC (Table 1). CD44 located in 11p13 showed eight copies in FC-IBC02, ten copies in the triple-negative IBC cells FC-IBC01 and three copies in SUM149; CD44 showed 1–2 copies in the ErbB2 + IBC and non-IBC, except MDA-MB468 (4.5 copies). Additionally, FC-IBC02 cells showed 3.5–4 copies of anaplastic lymphoma kinase (ALK) gene on chromosome 2p23.2 (Table 1).Fig. 4


Inflammatory breast cancer (IBC): clues for targeted therapies.

Fernandez SV, Robertson FM, Pei J, Aburto-Chumpitaz L, Mu Z, Chu K, Alpaugh RK, Huang Y, Cao Y, Ye Z, Cai KQ, Boley KM, Klein-Szanto AJ, Devarajan K, Addya S, Cristofanilli M - Breast Cancer Res. Treat. (2013)

Chromosome 8 in IBC and non-IBC cells. Copy number and loss of heterozygosity (LOH) were studied using Affymetrix CytoScan™ HD arrays. The chromosome 8 in different IBC and non-IBC cells is shown
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4273486&req=5

Fig4: Chromosome 8 in IBC and non-IBC cells. Copy number and loss of heterozygosity (LOH) were studied using Affymetrix CytoScan™ HD arrays. The chromosome 8 in different IBC and non-IBC cells is shown
Mentions: High-resolution arrays were used to evaluate copy number and LOH in FC-IBC02 cells and other triple-negative (Mary X, SUM149, FC-IBC01) and ErbB2-positive (MDA-IBC3, SUM190, KPL4, KMO-015) IBC cell lines. Also, non-IBC cells (MFC-7, MDA-MB231, MDA-MB468, SUM159) were included in these studies to compare the profiles between IBC and non-IBC cells. FC-IBC02 cells showed complicated genomic alterations in all chromosomes with the exception of chromosome 12 (Suppl. Fig. 2). Gains/amplifications were more common than deletions/losses; FC-IBC02 cells showed scattered genomic profile (deletions) on 11q chromosome arm known as chromothripsis; the copy number profile across this chromosome arm shows many positions at which copy number changes between one or two copies (Suppl. Fig. 2). Copy number and LOH studies were also performed for Mary X (Suppl. Fig. 3), SUM149 (Suppl. Fig. 4) and FC-IBC01 (Suppl. Fig. 5). Most of the IBC cells showed multiple amplifications of 8q having 3–10 copies of this chromosomal arm (Fig. 4). The 8q is the location of the oncogene MYC, MTDH1, PVT1, FAK1 (also known as PTK2K) and ATAD2 between other genes. In contrast, the non-IBC cell lines studied showed only 1–4 copies of 8q (Fig. 4). IBC cells showed 2.5–7 copies of the oncogene MYC and, although MYC was also amplified in non-IBC cells, the number of copies was lower in non-IBC (1–3 copies) with the exception of SUM159 cells that have a focal MYC amplification (Table 1). PTK2/FAK1 also showed more copies in IBC (2.5–7 copies) than in non-IBC cells (1–2.5 copies) (Table 1). Metadherin (MTDH1) showed 2.5–6 copies in IBC and 1–3 copies in non-IBC cell lines; ATAD2 showed 2.5–6 copies in IBC and 1–3.5 copies in non-IBC (Table 1). CD44 located in 11p13 showed eight copies in FC-IBC02, ten copies in the triple-negative IBC cells FC-IBC01 and three copies in SUM149; CD44 showed 1–2 copies in the ErbB2 + IBC and non-IBC, except MDA-MB468 (4.5 copies). Additionally, FC-IBC02 cells showed 3.5–4 copies of anaplastic lymphoma kinase (ALK) gene on chromosome 2p23.2 (Table 1).Fig. 4

Bottom Line: Also, CD44 was amplified in triple-negative IBC cells (10-3 copies).Additionally, FC-IBC02 showed amplification of ALK and NOTCH3.These results indicate that MYC, ATAD2, CD44, NOTCH3, ALK and/or FAK1 may be used as potential targeted therapies against IBC.

View Article: PubMed Central - PubMed

Affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Sandra.Fernandez@jefferson.edu

ABSTRACT
Inflammatory breast cancer (IBC) is the most aggressive type of advanced breast cancer characterized by rapid proliferation, early metastatic development and poor prognosis. Since there are few preclinical models of IBC, there is a general lack of understanding of the complexity of the disease. Recently, we have developed a new model of IBC derived from the pleural effusion of a woman with metastatic secondary IBC. FC-IBC02 cells are triple negative and form clusters (mammospheres) in suspension that are strongly positive for E-cadherin, β-catenin and TSPAN24, all adhesion molecules that play an important role in cell migration and invasion. FC-IBC02 cells expressed stem cell markers and some, but not all of the characteristics of cells undergoing epithelial mesenchymal transition (EMT). Breast tumor FC-IBC02 xenografts developed quickly in SCID mice with the presence of tumor emboli and the development of lymph node and lung metastases. Remarkably, FC-IBC02 cells were able to produce brain metastasis in mice on intracardiac or intraperitoneal injections. Genomic studies of FC-IBC02 and other IBC cell lines showed that IBC cells had important amplification of 8q24 where MYC, ATAD2 and the focal adhesion kinase FAK1 are located. MYC and ATAD2 showed between 2.5 and 7 copies in IBC cells. FAK1, which plays important roles in anoikis resistance and tumor metastasis, showed 6-4 copies in IBC cells. Also, CD44 was amplified in triple-negative IBC cells (10-3 copies). Additionally, FC-IBC02 showed amplification of ALK and NOTCH3. These results indicate that MYC, ATAD2, CD44, NOTCH3, ALK and/or FAK1 may be used as potential targeted therapies against IBC.

Show MeSH
Related in: MedlinePlus