ABSTRACT
The two main histological types of infiltrating breast cancer, lobular (ILC) and the more common ductal (IDC) carcinoma are morphologically and clinically distinct. To assess the molecular alterations associated with these breast cancer subtypes, we conducted a whole-genome study of 166 archival estrogen receptor (ER)-positive tumors (89 IDC and 77 ILC) using the Affymetrix GeneChip(R) Mapping 10K Array to identify sites of loss of heterozygosity (LOH) that either distinguished, or were shared by, the two phenotypes. We found single nucleotide polymorphisms (SNPs) of high-frequency LOH (>50%) common to both ILC and IDC tumors predominately in 11q, 16q, and 17p. Overall, IDC had a slightly higher frequency of LOH events across the genome than ILC (fractional allelic loss = 0.186 and 0.156). By comparing the average frequency of LOH by chromosomal arm, we found IDC tumors with significantly (P < 0.05) higher frequency of LOH on 3p, 5q, 8p, 9p, 20p, and 20q than ILC tumors. We identified additional chromosomal arms differentiating the subtypes when tumors were stratified by tumor size, mitotic rate, or DNA content. Of 5,754 informative SNPs (>25% informativity), we identified 78 and 466 individual SNPs with a higher frequency of LOH (P < 0.05) in ILC and IDC tumors, respectively. Hierarchical clustering of these 544 SNPs grouped tumors into four major groups based on their patterns of LOH and retention of heterozygosity. LOH in chromosomal arms 8p and 5q was common in higher grade IDC tumors, whereas ILC and low-grade IDC grouped together by virtue of LOH in 16q.
Subject(s)
Breast Neoplasms/genetics , Carcinoma, Ductal, Breast/genetics , Carcinoma, Lobular/genetics , Loss of Heterozygosity , Receptors, Estrogen/analysis , Breast Neoplasms/pathology , Carcinoma, Lobular/pathology , Case-Control Studies , DNA, Neoplasm/metabolism , Female , Gene Expression Profiling , Humans , Immunohistochemistry , Polymorphism, Single Nucleotide , Receptors, Estrogen/genetics , Tissue Array AnalysisABSTRACT
A panel of murine monoclonal antibodies (MAbs) against porcine growth hormone (pGH) has been raised from BALB/c mice. MAbs were characterized for binding to growth hormones (GH), prolactins (PRL), and placental lactogen (PL) from different species and to the N-terminal peptides of GH. From their patterns of cross-reactivity MAbs were assigned into nine specificity groups. The sharing of pGH epitopes among hormones of different species was related to the sequence similarity to pGH, i.e., overlap was greatest for equine, ruminant, and rodent GHs and least for human GH, ovine, and porcine PRLs, and human PL. Partial epitope mapping was carried out by relating hormone cross-reactivity patterns with amino acid sequences. Two epitopes were localized to interhelical loops, around valine-73 and glycine-130, respectively. Direct mapping with synthetic peptides localized other epitopes (Groups 7, 8, and 9) to the N-terminal region of the GH molecule. Selected MAbs were studied for the enhancement of the somatogenic activity of pGH in the dwarf mouse bioassay, measuring weight gain and sulphate incorporation into costal cartilage. Only those antibodies with specificities for GHs and not PRL or PL showed significant enhancement in this assay.
