Amplification of the prolactin receptor gene in mammary lobular neoplasia

Abstract

The identification of lobular carcinoma in situ (LCIS) in a patient's specimen confers an appreciable increased risk of development of future invasive mammary carcinoma. However, the study of LCIS presents a challenge as it is usually only recognized in fixed specimens. Recent advances in high throughput genomics have made possible comprehensive copy number analysis of lesions such as this. Using array comparative genomic hybridization (aCGH), we characterized eight cases of lobular carcinoma (four invasive and four non-invasive) from microdissected samples of archival specimens and validated our results by quantitative real-time PCR (qRT-PCR). Immunohistochemistry (IHC) was performed on an independent set of 80 in situ ductal (DCIS) and lobular breast lesions to confirm our results. Amplification of the prolactin receptor gene (PRLr) was identified in 4/4 cases of LCIS by aCGH. We confirmed this amplification by qRT-PCR and demonstrated PRLr expression in 29/40 (73%) cases of lobular neoplasia by IHC. Amplification of PRLr was neither detected in 10 cases of DCIS nor in 5 areas of normal breast tissue by qRT-PCR and only 14/40 (35%) cases of DCIS showed PRLr expression by IHC (P = 0.0008). Our study suggests the prolactin receptor gene is a molecular target that may be important in the pathogenesis and progression of lobular neoplasia. Investigation of the status of this gene in cases of DCIS has indicated that it may not be as important in the progression of this type of breast cancer, supporting the view that lobular and ductal carcinomas may evolve along separate pathways.

Truncating Prolactin Receptor Mutations Promote Tumor Growth in Murine Estrogen Receptor-Alpha Mammary Carcinomas

“…There is also support for an association between PRLR allelic variations and breast cancer risk (Bogorad et al, 2008; Lee et al, 2007; Mong et al, 2011; Vaclavicek et al, 2006). In lobular neoplasia, amplification of PRLR may also be important for pathogenesis and progression (Tran-Thanh et al, 2011). Additionally, mouse mammary cancer models support a role for Prlr signaling in tumor progression.…”

Molecular drivers of lobular carcinoma in situ

“…Intriguingly, LCIS and ILC lesions retained STAT5 expression in 32 % and 17 % of the samples, respectively [ 89 ]. Amplification of prolactin receptor - an upstream activator of STAT5a signaling in breast tissue - is also observed in LCIS and ILC lesions, but not in DCIS lesions [ 92 , 93 ]. These data suggest that STAT5a might provide survival signals to neoplastic cells in LCIS.…”

Lactogens and estrogens in breast cancer chemoresistance

“…The PRLR is expressed in the normal breast, and both the long form and several of the isoforms are variably expressed in carcinomas [33]. Amplification of the PRLR suggests its importance in the pathogenesis and/or progression of lobular carcinomas [34]. …”