Heterogeneity of mammary lesions represent molecular differences

Ruria Namba, Jeannie E. Maglione, Ryan R. Davis, Colin A. Baron, Stephenie Liu, Condie E. Carmack, Lawrence J T Young, Alexander D Borowsky, Robert Cardiff, Jeffrey Gregg

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Background: Human breast cancer is a heterogeneous disease, histopathologically, molecularly and phenotypically. The molecular basis of this heterogeneity is not well understood. We have used a mouse model of DCIS that consists of unique lines of mammary intraepithelial neoplasia (MIN) outgrowths, the premalignant lesion in the mouse that progress to invasive carcinoma, to understand the molecular changes that are characteristic to certain phenotypes. Each MIN-O line has distinguishable morphologies, metastatic potentials and estrogen dependencies. Methods: We utilized oligonucleotide expression arrays and high resolution array comparative genomic hybridization (aCGH) to investigate whole genome expression patterns and whole genome aberrations in both the MIN-O and tumor from four different MIN-O lines that each have different phenotypes. From the whole genome analysis at 35 kb resolution, we found that chromosome 1, 2, 10, and 11 were frequently associated with whole chromosome gains in the MIN-Os. In particular, two MIN-O lines had the majority of the chromosome gains. Although we did not find any whole chromosome loss, we identified 3 recurring chromosome losses (2F1-2, 3E4, 17E2) and two chromosome copy number gains on chromosome 11. These interstitial deletions and duplications were verified with a custom made array designed to interrogate the specific regions at approximately 550 bp resolution. Results: We demonstrated that expression and genomic changes are present in the early premalignant lesions and that these molecular profiles can be correlated to phenotype (metastasis and estrogen responsiveness). We also identified expression changes associated with genomic instability. Progression to invasive carcinoma was associated with few additional changes in gene expression and genomic organization. Therefore, in the MIN-O mice, early premalignant lesions have the major molecular and genetic changes required and these changes have important phenotypic significance. In contrast, the changes that occur in the transition to invasive carcinoma are subtle, with few consistent changes and no association with phenotype. Conclusion: We propose that the early lesions carry the important genetic changes that reflect the major phenotypic information, while additional genetic changes that accumulate in the invasive carcinoma are less associated with the overall phenotype.

Original languageEnglish (US)
Article number275
JournalBMC Cancer
Volume6
DOIs
StatePublished - 2006

Fingerprint

Breast
Neoplasms
Phenotype
Chromosomes
Carcinoma
Genome
Estrogens
Chromosomes, Human, Pair 11
Chromosomes, Human, Pair 3
Carcinoma, Intraductal, Noninfiltrating
Comparative Genomic Hybridization
Chromosomes, Human, Pair 2
Genomic Instability
Chromosomes, Human, Pair 1
Oligonucleotide Array Sequence Analysis
Molecular Biology
Breast Neoplasms
Neoplasm Metastasis
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Namba, R., Maglione, J. E., Davis, R. R., Baron, C. A., Liu, S., Carmack, C. E., ... Gregg, J. (2006). Heterogeneity of mammary lesions represent molecular differences. BMC Cancer, 6, [275]. https://doi.org/10.1186/1471-2407-6-275

Heterogeneity of mammary lesions represent molecular differences. / Namba, Ruria; Maglione, Jeannie E.; Davis, Ryan R.; Baron, Colin A.; Liu, Stephenie; Carmack, Condie E.; Young, Lawrence J T; Borowsky, Alexander D; Cardiff, Robert; Gregg, Jeffrey.

In: BMC Cancer, Vol. 6, 275, 2006.

Research output: Contribution to journalArticle

Namba, R, Maglione, JE, Davis, RR, Baron, CA, Liu, S, Carmack, CE, Young, LJT, Borowsky, AD, Cardiff, R & Gregg, J 2006, 'Heterogeneity of mammary lesions represent molecular differences', BMC Cancer, vol. 6, 275. https://doi.org/10.1186/1471-2407-6-275
Namba R, Maglione JE, Davis RR, Baron CA, Liu S, Carmack CE et al. Heterogeneity of mammary lesions represent molecular differences. BMC Cancer. 2006;6. 275. https://doi.org/10.1186/1471-2407-6-275
Namba, Ruria ; Maglione, Jeannie E. ; Davis, Ryan R. ; Baron, Colin A. ; Liu, Stephenie ; Carmack, Condie E. ; Young, Lawrence J T ; Borowsky, Alexander D ; Cardiff, Robert ; Gregg, Jeffrey. / Heterogeneity of mammary lesions represent molecular differences. In: BMC Cancer. 2006 ; Vol. 6.
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abstract = "Background: Human breast cancer is a heterogeneous disease, histopathologically, molecularly and phenotypically. The molecular basis of this heterogeneity is not well understood. We have used a mouse model of DCIS that consists of unique lines of mammary intraepithelial neoplasia (MIN) outgrowths, the premalignant lesion in the mouse that progress to invasive carcinoma, to understand the molecular changes that are characteristic to certain phenotypes. Each MIN-O line has distinguishable morphologies, metastatic potentials and estrogen dependencies. Methods: We utilized oligonucleotide expression arrays and high resolution array comparative genomic hybridization (aCGH) to investigate whole genome expression patterns and whole genome aberrations in both the MIN-O and tumor from four different MIN-O lines that each have different phenotypes. From the whole genome analysis at 35 kb resolution, we found that chromosome 1, 2, 10, and 11 were frequently associated with whole chromosome gains in the MIN-Os. In particular, two MIN-O lines had the majority of the chromosome gains. Although we did not find any whole chromosome loss, we identified 3 recurring chromosome losses (2F1-2, 3E4, 17E2) and two chromosome copy number gains on chromosome 11. These interstitial deletions and duplications were verified with a custom made array designed to interrogate the specific regions at approximately 550 bp resolution. Results: We demonstrated that expression and genomic changes are present in the early premalignant lesions and that these molecular profiles can be correlated to phenotype (metastasis and estrogen responsiveness). We also identified expression changes associated with genomic instability. Progression to invasive carcinoma was associated with few additional changes in gene expression and genomic organization. Therefore, in the MIN-O mice, early premalignant lesions have the major molecular and genetic changes required and these changes have important phenotypic significance. In contrast, the changes that occur in the transition to invasive carcinoma are subtle, with few consistent changes and no association with phenotype. Conclusion: We propose that the early lesions carry the important genetic changes that reflect the major phenotypic information, while additional genetic changes that accumulate in the invasive carcinoma are less associated with the overall phenotype.",
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AU - Davis, Ryan R.

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AU - Borowsky, Alexander D

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N2 - Background: Human breast cancer is a heterogeneous disease, histopathologically, molecularly and phenotypically. The molecular basis of this heterogeneity is not well understood. We have used a mouse model of DCIS that consists of unique lines of mammary intraepithelial neoplasia (MIN) outgrowths, the premalignant lesion in the mouse that progress to invasive carcinoma, to understand the molecular changes that are characteristic to certain phenotypes. Each MIN-O line has distinguishable morphologies, metastatic potentials and estrogen dependencies. Methods: We utilized oligonucleotide expression arrays and high resolution array comparative genomic hybridization (aCGH) to investigate whole genome expression patterns and whole genome aberrations in both the MIN-O and tumor from four different MIN-O lines that each have different phenotypes. From the whole genome analysis at 35 kb resolution, we found that chromosome 1, 2, 10, and 11 were frequently associated with whole chromosome gains in the MIN-Os. In particular, two MIN-O lines had the majority of the chromosome gains. Although we did not find any whole chromosome loss, we identified 3 recurring chromosome losses (2F1-2, 3E4, 17E2) and two chromosome copy number gains on chromosome 11. These interstitial deletions and duplications were verified with a custom made array designed to interrogate the specific regions at approximately 550 bp resolution. Results: We demonstrated that expression and genomic changes are present in the early premalignant lesions and that these molecular profiles can be correlated to phenotype (metastasis and estrogen responsiveness). We also identified expression changes associated with genomic instability. Progression to invasive carcinoma was associated with few additional changes in gene expression and genomic organization. Therefore, in the MIN-O mice, early premalignant lesions have the major molecular and genetic changes required and these changes have important phenotypic significance. In contrast, the changes that occur in the transition to invasive carcinoma are subtle, with few consistent changes and no association with phenotype. Conclusion: We propose that the early lesions carry the important genetic changes that reflect the major phenotypic information, while additional genetic changes that accumulate in the invasive carcinoma are less associated with the overall phenotype.

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