Abstract
IntroductionAlthough lobular carcinoma in situ (LCIS) has traditionally been viewed as a marker of breast cancer risk, recent clinical, pathological and genetic analyses have supported the concept that LCIS is a low risk, direct precursor of invasive lobular carcinoma. Global gene expression profiling of LCIS has not been performed.MethodsWe analysed the comprehensive gene expression profile of a unique case of mass-forming LCIS using serial analysis of gene expression (SAGE). This SAGE library is publicly available online. By comparing the gene expression profile of LCIS to that of benign breast epithelium and stroma, we identified several genes up and down regulated in LCIS. Differential expression of selected genes not previously studied in LCIS was validated at the protein level by immunohistochemistry and at the RNA level by quantitative reverse transcriptase PCR (RT-PCR).ResultsWe identified down regulation of claudin 4 and overexpression of matrix metalloproteinase 9 in LCIS relative to normal breast epithelium and stroma. We validated these findings by immunohistochemistry in a separate series of 11 and 19 LCIS cases, respectively. Overexpression of matrix metalloproteinase 9 was further confirmed by quantitative RT-PCR analysis of the index case.ConclusionsWe have created the first global gene expression profile of LCIS, and demonstrated down regulation of cell junction proteins (an expected result) and overexpression of matrix metalloproteinase 9 (an unexpected result). Additional analysis of this data made available as an online resource should facilitate further molecular characterisation of LCIS.
Highlights
Lobular carcinoma in situ (LCIS) has traditionally been viewed as a marker of breast cancer risk, recent clinical, pathological and genetic analyses have supported the concept that lobular carcinoma in situ (LCIS) is a low risk, direct precursor of invasive lobular carcinoma
We identified down regulation of claudin 4 and overexpression of matrix metalloproteinase 9 in LCIS relative to normal breast epithelium and stroma
Our rationale was that the enriched LCIS sample we used for serial analysis of gene expression (SAGE) still contained some contaminating normal breast stroma and myoepithelium, so inclusion of stromal and myoepithelial SAGE libraries in the comparison would negate their contribution and allow meaningful distinctions between LCIS cells and normal breast epithelial cells
Summary
Lobular carcinoma in situ (LCIS) has traditionally been viewed as a marker of breast cancer risk, recent clinical, pathological and genetic analyses have supported the concept that LCIS is a low risk, direct precursor of invasive lobular carcinoma. Lobular carcinoma in situ (LCIS) is characterised by small, discohesive epithelial cells that fill, distend and distort the terminal duct lobular units of the breast [1,2]. Unlike ductal carcinoma in situ (DCIS), a localised proven precursor to invasive breast carcinoma, LCIS tends to be multifocal and bilateral, and typically is neither calcified on mammography nor mass forming on clinical or gross pathological examination. Less well-developed examples of the same process, in which there is insufficient distention and ALH: atypical lobular hyperplasia; bp: base pair; CGAP: cancer genome anatomy project; CGH: Comparative Genomic Hybridisation; DCIS: ductal carcinoma in situ; DGED: Digital Gene Expression Displayer; H & E: haematoxylin & eosin; IDC: invasive ductal carcinoma; LCIS: lobular carcinoma in situ; LSAGE: long serial analysis of gene expression; MMP: matrix metalloproteinase; OCT: optimal controlled temperature medium; RT-PCR: reverse transcriptase polymerase chain reaction; SAGE: serial analysis of gene expression; TIMPS: tissue inhibitors of metalloproteinases
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