It is presumed that MBC is biologically similar to FBC. However, there are differences between the two: a higher frequency of expression of ER (81%) and progesterone receptor (PR) (74%) is in MBC (for review see [5]). In contrast to women, men do not have a higher incidence of ER-positive tumors with advancing age. The relationship of ER with overall survival is uncertain. In a multi-institutional study, Donegan and colleagues [6] found that ER was associated with better survival; however, in a series of 229 patients from the Princess Margaret Hospital no significance was found in multivariate analysis [7]. Wang-Rodriguez and colleagues found better survival in ER-positive patients but did not find a benefit from treatment with Tamoxifen [8]. Proliferative activity is higher in ER⁺/PR⁺MBCs than in ER^-/PR^- tumors [9]. More recently, Pich and colleagues [4] found no correlation between the expression of ER, PR or androgen receptor (AR) with overall survival. They concluded that MBCs are biologically different from FBCs and questioned the rationale for the use of anti-hormonal (Tamoxifen) therapy in MBCs.

One block from each case was selected to analyze the expression of PSA, PSAP and AR on serial sections by immunohistochemical methods. Paraffin-embedded sections (4 μm thick) after peroxide blocking (3% hydrogen peroxide in methanol) and antigen retrieval (a microwave oven pressure cooker with Citra [BioGenex^®]) were incubated with serum block to reduce non-specific staining before exposure to the primary antibody. Polyclonal antibodies against PSA and PSAP (both from Dako Corp^®; 1:1800), and monoclonal antibody against AR (Novocastra^®, 1:10) were used. Biotin-labeled secondary antibody and ABC complex (Vector^®) followed by exposure to diaminobenzidine tetrahydrochloride (Sigma Corp^®) were used to detect the antigen. The slides were counter-stained with hematoxylin and mounted in Permount. Phosphate-buffered saline and rabbit or mouse isotypic antibody were used to confirm specificity of the staining. Normal prostatic tissue (from other patients) was used for positive control for AR, PSA and PSAP.

The criteria used to evaluate expression were as follows. Expression of PSA and PSAP was classified as focal or diffuse depending on the fraction of the tumor cells stained. The criteria for AR positivity were based on the intensity and percentage of tumor cells showing expression. The intensity was graded as negative, weak, moderate or strong. Tumors that had more than 10% of cells exhibiting moderate or strong intensity of expression were considered positive.

We reviewed the databases of the Northwestern Memorial Hospital as well as Lakeside VA Hospital to obtain the follow-up information of MBC. Follow-up information was available for 17 cases. The overall follow-up ranged from 12 to 168 months; the median follow-up was 48 months.

AR expression, like that of ER and PR, was seen in the nuclei of breast epithelial cells (Fig. ​(Fig.1)1) and in scattered stromal cells. The expression in tumor cells was seen in 19 of 26 cases (73%).

In contrast, PSA expression was cytoplasmic (Fig. ​(Fig.2).2). Normal breast tissue, both ducts and stromal elements (including adipocytes and vascular endothelium), did not show any expression of this protein. Expression was observed in six (23%) cases of tumors; five of these (19%) showed focal expression, and one (4%) demonstrated diffuse staining. These PSA-positive cases were histologically grade II and III tumors (three cases each). PSAP expression was not detected in any of the cases studied.

PSA and PSAP are androgen-regulated proteins and are thought to be relatively specific to the prostate. Although serum PSA in males is predominantly derived from the prostate, there are additional sources of this protein: low levels are found even in females [18-20]. PSA has been shown to be present in several sites including salivary glands and the breast. Whether PSA is expressed in normal healthy breast is controversial [21], although Yu and colleagues [22], using quantitative methods and polymerase chain reaction, were able to demonstrate PSA in normal breast tissues in 33% of cases. PSA has been demonstrated in milk from lactating breast [18-20], in nipple aspiration fluid [23], and in apocrine foci within fibrocystic disease of the breast [24] in addition to breast cancer (for review see [25]). In male breast, Gatalica and colleagues [16] have reported focal strong PSA expression in normal and hyperplastic ductal epithelium in 5 of 18 cases of gynecomastia. In our study we did not observe any immunoreactivity for PSA in peritumoral breast tissues.

PSA from breast tumors has the same molecular characteristics as seminal or prostatic PSA. In the prostatic secretions PSA is important in the dissolution of the gel structure of freshly ejaculated semen [26], through the specific proteolysis of both high molecular mass semenogelin and fibronectin. PSA, like some other proteases, can also digest other substrates. It can, for example, digest insulin-like growth factor-binding proteins, leading to the release of these growth factors [27]. Similarly, digestion of the basement membrane and extracellular matrix proteins might facilitate cell migration and invasion [27]. However, PSA has also been shown to inhibit the endothelial cell response to angiogenic stimulation by fibroblast growth factor-2 and vascular endothelial growth factor [28]. It has been suggested that PSA might be an endogenous anti-angiogenic compound. This might contribute to the association between PSA and prognosis seen in some studies [29,30].

PSA expression in FBC has been associated with younger age [31,32] in some studies but with postmenopausal status in others [33]. Alanen and colleagues [33] and Howarth and colleagues [34] found a correlation of PSA expression in FBCs with differentiated tumor types and low tumor grade. Similarly, Yu and colleagues [30] reported that the presence of PSA was significantly associated with smaller tumors, tumors with low S-phase fraction, diploid tumors, younger patient age, and tumors with lower cellularity. In their study, PSA expression was associated with good prognosis in FBC even after multivariate analysis. All the MBC cases in our study that expressed PSA were histologically of grade II or III. Our study, although limited by size and follow-up information, could not identify a prognostic role for PSA.

PSA expression in FBCs is strongly correlated with expression of ER and AR. Most PSA-producing FBCs are positive for steroid hormone receptor (ER/AR), but not all tumors that are positive for steroid hormone receptors produce PSA [35]. Hall and colleagues [36] have reported an even stronger association of AR and PSA expression with AR expression seen in 98% of FBCs expressing PSA. In the present study, of the six cases that were positive for PSA, AR expression was seen in only four. These observations are consistent with the hypothesis [4] that MBC is biologically different from FBC. The presence of PSA expression in breast carcinomas (both FBCs and MBCs) in the absence of AR expression would suggest the presence of an AR-independent pathway for PSA expression. Yu and colleagues [37] have shown the expression of PSA in normal breast tissue from a woman taking Brevicon, a progesterone-containing contraceptive. Of the two cases in our series that were PSA⁺/AR⁺, only one was PR⁺. However, both expressed ER. This is consistent with the reported expression of PSA in breast cancer cell lines after stimulation by norethindrone or ethinylestradiol [37].