The role of prolactin (PRL) in human breast cancer is now becoming more clearly defined. Recent epidemiologic evidence clearly shows that in both pre- and post-menopausal women with serum prolactin levels in the highest quartile have a significant increased risk of developing breast cancer [1, 2]. PRL, acting through is receptors, has definitively been shown to increase cell proliferation and decrease apoptosis in breast cancer cells in culture [3, 4]. Additionally, PRL is a pro-angiogenesis factor both in normal and cancerous mammary tissue [5, 6]. We  and others  have shown the existence of several receptor isoforms whose involvement in PRL-induced cell proliferation and decreased apoptosis remains to be fully defined.
The PRLR is a member of the class I cytokine/hematopoietic receptor superfamily, characterized by a single hydrophobic transmembrane region that separates the ligand-binding extracellular from the signaling intracellular domain. There are five cell-associated isoforms of the human PRLR, long (LF), intermediate, ΔS1, and two short forms (SF1a and SF1b) [4, 9] that differ only in their C-terminal cytoplasmic domains. The expression of the PRLR is regulated by PRL itself where low levels of PRL upregulate and high levels of PRL downregulate the receptor . The three major cell associated isoforms of the PRLR, the LF, that signals for all known functions including growth and differentiation, and two short forms, SF1a and SF1b, whose functions, other than their ability to act as dominant negatives for differentiation in transfected cultured cells [7, 8, 11, 12], are still largely undefined. Studies from our laboratory and from others [7, 12] have demonstrated that mRNA for the three specific isoforms of the PRLR is expressed in both normal and cancerous human breast cells and tissues.
Ductal and lobular carcinomas are the most common histological types of breast cancer. This nomenclature and system of classification is not without controversy since both originate from the same anatomical structure, the terminal ductal lobular unit. Most pathologists label tumors by their grade, size, stage, and hormone receptor (estrogen receptor, ER; progesterone receptor, PR and Her2) status. Lobular carcinomas represent approximately 10% of breast cancers and are biologically distinct from ductal carcinomas  that have defined tumor foci. Lobular carcinomas appear spindly, tend to grow in sheets and, therefore, do not present as a mass. As a result, lobular carcinomas are more difficult to diagnose clinically and tend to be treated more aggressively . But in spite of this, lobular carcinomas can be treated successfully by surgical or chemotherapeutic intervention. While there appears to be no survival advantage between the two types of cancers, development and progression of the disease varies [14, 15].
On a molecular level, there are many differences between ductal and lobular carcinomas. Using microarray techniques and three types of statistical analyses, Zhao et al.  demonstrated that genes differentially expressed between ductal and lobular carcinomas code for proteins involved in cell motility/adhesion, fatty acid transport and metabolism, immune response, and electron transport. Most genes that significantly distinguish lobular carcinoma were involved in cell growth and immune response, but their function remains unknown.
Previous work using B6.2, a PRLR monoclonal antibody characterized in our laboratory  that is unable to distinguish the various isoforms, indicated a lack of correlation between PRLR expression and tumor grade, size or axillary lymph node status . However, distinct differences were observed for the site of PRLR expression among normal, benign, and malignant breast tissue. Previous studies had suggested that in some subgroups of breast cancer patients, detection of PRLR may have prognostic significance . With the discovery of the various isoforms of the PRLR, a more detailed analysis of the cellular localization of the receptor as well as possible differences between subtypes of breast cancer was warranted. To facilitate these studies we developed and characterized PRLR isoform specific polyclonal antibodies that reveal that three isoforms, LF, SF1a and SF1b, are differentially expressed in ductal and lobular carcinoma tissues.