Amplification of the Prolactin Receptor Gene in Mammary Lobular Neoplasia.

Abstract

Abstract Background: Lobular carcinoma in situ (LCIS) has long been considered a marker of increased risk of cancer in both breasts. However, recent studies have shown that it can behave as a non-obligate precursor lesion as well. The biology and natural history of LCIS still remains ill defined in part because it is a challenging lesion to study as it usually does not have an identifiable gross appearance and is only recognized in fixed tissue specimens.Material and Methods: Using array comparative genomic hybridization (aCGH) we have analyzed regions of amplification found in LCIS and adjacent invasive lobular carcinoma (ILC) in a series of thirteen cases of archival patient samples from our institution. Degenerate oligonucleotide primed (DOP) PCR was performed for whole genome amplification of the extracted DNA from microdissected tissue samples prior to microarray analysis. Analysis of microarray data was performed using Significance Analysis of Microarrays (SAM). Of the ten most amplified genes in LCIS (highest SAM scores), one was selected for quantitative real time PCR (Q-PCR) validation due to the limited amount of material available from these cases. Q-PCR validation was performed on samples from 8 cases of LCIS and invasive lobular carcinoma and 12 archival cases of ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) for comparison.Results: Amongst the 10 genes with the highest SAM scores, the prolactin receptor gene (PRLR) was selected for further Q-PCR validation in our limited samples. Amplification of PRLR was confirmed by Q-PCR in 4/8 (50%) of cases of LCIS and 4/8 (50%) cases of ILC, compared to 0/12 (0%) cases of DCIS and 3/12 (25%) cases of IDC. When LCIS and ILC were combined into one group, there was more amplification of the prolactin receptor gene when compared to the DCIS and IDC group (p= 0.01). The level of amplification between the two groups also differed in the range of copy number values, which was lower in the ductal group (0.78-1.58, n=24) compared to the lobular group (0.92-3.68, n=16) (p<0.05).Conclusion: We have identified the prolactin receptor as a potential molecular target in lobular neoplasia using array comparative genomic hybridization. In contrast, we have shown that the prolactin receptor may not be as important for the progression of ductal lesions. These results support the view that lobular and ductal carcinoma evolve along separate pathways. Validation of the expression of PRLR in a larger number of LCIS cases is warranted. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4151.