Breast carcinoma is considered to be one of the main causes of cancer mortality. Assessment of the risk of development of invasive breast cancer has become a significant problem. In the last decade, screening programs have been intensified since mammographic screening significantly contributes on breast cancer mortality [1, 2]. The major aim of these programs is the detection of breast carcinomas in earlier and probably better curable stage . In the past 20 years, concomitant with the wide use of screening mammography, the incidence of ductal carcinoma in situ (DCIS) has risen dramatically, in asymptomatic women to 20-25% of all screening detected breast cancers . Therefore, the mammographically diagnosed non-palpable breast carcinomas are increasingly considered as a unique entity of major clinical interest. Non-palpable breast carcinomas consists a heterogeneous group of lesions with variable findings and different prognosis. Mammographically detected density is a risk factor for breast cancer and is attributed to alterations in the composition of breast tissue [5, 6]. Previous studies seeking to understand the biological basis of mammographic density (MD) have focused on associations with epithelial and stromal changes [7, 8]. Another mammographic finding of higher risk than tissue density for breast cancer is malignant-appearing microcalcifications (MAMCs), which are associated with in situ and invasive breast carcinomas in asymptomatic women . MAMCs are the primary indication for approximately 50% of the breast biopsies carried out for non-palpable mammographic abnormalities, although they do not always represent malignancy .
A wide range of prognostic markers have been proposed for non-palpable breast carcinomas. The clinically available markers such as histological type, size, auxiliary node involvement and cytological grading are not sufficient, considering the biological complexity of this clinical entity . Several biological markers such as estrogen receptor alpha (ERα), progesterone receptor (PR), and the ErbB family of receptor tyrosine kinases have been evaluated by means of immunohistochemistry in non-palpable breast carcinomas and found to correlate with mammographic findings of higher risk such as MAMCs [12, 13]. Estrogens contribute to the initiation and promotion of cancer through triggering the proliferation of breast epithelium and stroma. Consequently they increase the changes of mutation in rapidly proliferating epithelium and those effects accumulate with increasing cumulative exposure to estrogens . The over-expression of c-erbB2 (HER-2/neu) is associated with more aggressive tumor behavior .
Although breast cancer is a direct manifestation of alterations in the expression of multiple genes and cellular pathways within the cancer cell, it is now recognized that perturbations in stromal-epithelial interactions also influence tumorigenesis and progression through direct effects on growth factor-induced signaling pathways and indirect effects mediated through cell adhesion and structure [8, 16, 17].
Several studies have demonstrated abnormal expression of the matrix-secreted proteoglycans versican and decorin in various cancer types such as prostate [18, 19], breast [20, 21], gastric , colorectal [23, 24], ovarian , pancreatic , laryngeal [27, 28] and testicular tumors . Versican is synthesized mainly by stromal cells and is capable to regulate tumor cell growth and motility. Versican may facilitate the local expansion of cancer cells and, subsequently, the invasion and formation of distant metastases by decreasing cell-matrix adhesion, sufficient to promote cancer cell migration through the extracellular matrix [30–32]. This notion is supported by observations that relapse in women with stage I node-negative breast cancer is related to the level of versican accumulated in peritumoral stroma  and the increased levels of peritumoral versican are also predictive of poor prognosis in patients with early-stage prostatic cancer . In contrast, decorin, which is mainly over-expressed by activated fibroblasts in various cancer types, is considered to be a tumor suppressor proteoglycan [18, 22–24, 26–29, 32]. Others have previously shown that matrix proteoglycans lumican and decorin are abundant components of breast tissue stroma and that altered expression of lumican and decorin is associated with tumor progression and outcome [33–35]. These proteoglycans are important for stromal integrity through their implication in fibrillar collagen cross linking. Decorin is also a powerful regulator of growth factor-mediated signaling .
We therefore wished to examine the relationship between mammographic findings suggestive of malignancy in non-palpable breast carcinomas and the expression of stromal proteoglycans versican and decorin, to establish whether the increased risk attributed to these findings might reflect stromal alterations. The expression of both proteoglycans was correlated with tumor characteristics and established biomarkers of the disease to evaluate their implication in breast cancer biology. Both proteoglycans were accumulated in MD and MAMCs although decorin was most likely associated with tissue fibrosis and matrix deposition. Versican was specifically accumulated in MD and MAMCs in the presence of malignant transformation and was significantly correlated with increased tumor grade and invasiveness. The over-expression of both proteoglycans is associated with the presence of ERα and PR in tumor cells in MAMCs.