Integrated Profiling of Basal and Luminal Breast Cancers

Abstract

Basal and luminal are two molecular subtypes of breast cancer with opposite histoclinical features. We report a combined, high-resolution analysis of genome copy number and gene expression in primary basal and luminal breast cancers. First, we identified and compared genomic alterations in 45 basal and 48 luminal tumors by using 244K oligonucleotide array comparative genomic hybridization (aCGH). We found various genome gains and losses and rare high-level gene amplifications that may provide therapeutic targets. We show that gain of 10p is a new alteration in basal breast cancer and that a subregion of the 8p12 amplification is specific of luminal tumors. Rare high-level amplifications contained BCL2L2, CCNE, EGFR, FGFR2, IGF1R, NOTCH2, and PIK3CA. Potential gene breaks involved ETV6 and FLT3. Second, we analyzed both aCGH and gene expression profiles for 42 basal and 32 luminal breast cancers. The results support the existence of specific oncogenic pathways in basal and luminal breast cancers, involving several potential oncogenes and tumor suppressor genes (TSG). In basal tumors, 73 candidate oncogenes were identified in chromosome regions 1q21-23, 10p14, and 12p13 and 28 candidate TSG in regions 4q32-34 and 5q11-23. In luminal breast cancers, 33 potential oncogenes were identified in 1q21-23, 8p12-q21, 11q13, and 16p12-13 and 61 candidate TSG in 16q12-13, 16q22-24, and 17p13. HORMAD1 (P = 6.5 Â 10 À5 ) and ZNF703 (P = 7 Â 10 À4

A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines

“…Data generated with this platform not only provided a detailed characterisation of the genomic profiles of these cell lines, but also allowed for a direct integration of genomic and transcriptomic data. Our results demonstrate that breast cancer cell lines have genomic and transcriptomic features that recapitulate those of primary breast cancers [2, 4,34,35,45]. First, in accordance with previous studies [1, 4], we show that breast cancer cell lines can be subclassified in basal-like and luminal subgroups and that the genes associated with each subgroup are remarkably similar to those significantly expressed in primary basal-like and luminal breast cancers, respectively [3,5,6].…”

“…By correlating the awssmoothed log2 aCGH ratios (copy number states) with expression levels using Pearson's correlation, we identified 753 genes whose expression significantly positively correlates with copy number changes (adjusted P-value \0.05, Table 3; Supplementary Table S5). This gene list generated by this analysis was enriched for genes mapping to chromosomes 17 (10.36%), 8 (9.69%), 11 (9.56%), 1 (9.03%), 3 (7.57%) and 6 (7.04%), and, as expected, one of the genes that displayed the strongest correlation was ERBB2 (HER2) 4,34,35]. Furthermore, genes whose expression levels correlate with copy number and are amplified in breast cancer cell lines could be identified in a systematic fashion.…”

Increased insulin-like growth factor-1 receptor mRNA expression predicts poor survival in immunophenotypes of early breast carcinoma

“…Nevertheless, IGF1R may have some relevance in a subgroup of aggressive basal/triple-negative tumors. 2,37,38 It is noteworthy that in this study, phenotypes have been only stratified according to immunohistochemical and in situ hybridization (for HER2 tumors) results. In addition, besides the HR-positive status, Bcl2, p53 and Ki67 data were taken into consideration for classifying tumors into luminal A or luminal B, based on the important role of apoptosis and proliferation-related genes emphasized in previous studies, [39][40][41] and also supported by our study.…”

Molecular insights on basal-like breast cancer

“…Adélaïde et al [33] observed rare high-level amplifications in basal tumors affecting small regions, including PIK3CA (3q26), IGF1R (15q26), and CCNE1 (19q11-12), but also single genes, such as EGFR (7p11), FGFR2 (10q26), and BCL2L2 (14q11). EGFR, FGFR2, and IGF1R are tyrosine kinase receptors with a broad mitogenic and angiogenesis function and thus can serve as potential therapeutic targets.…”

“…In the same line, specific genomic losses were also detected in basal subtype. The loss of heterozygosity (LOH) at 4p and 5q has been able to define a subclass of BLBC [33,34]. Losses of 4p and 5q associated with BLBC targeted several genes including candidate or known tumor suppressing genes such as SLIT2 (4p15.31), GPR125 (4p15.31), RASA1 (5q14.3), and APC (5q22.2) [33].…”