This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.

Accumulation of hyaluronan (HA) in pericellular stroma and carcinoma cells is predictive of unfavorable patient prognosis in many epithelial cancers. However, it is not known whether the HA originates from carcinoma or stromal cells, or whether increased expression of hyaluronan synthase proteins (HAS1-3) contributes to HA accumulation. In this study, localization and expression of HAS1-3 were evaluated immunohistochemically in 278 cases of human breast cancer, and correlated with prognostic factors and patient outcome. Both carcinoma cells and stromal cells were HAS-positive. In carcinoma cells, HAS1 and HA stainings correlated with each other, and HAS1 associated with estrogen receptor negativity, HER2 positivity, high relapse rate, and short overall survival. In stromal cells, the staining levels of all HAS isoforms correlated with the stromal HA staining, stromal cell CD44, high relapse rate, and short overall survival of the patients. In addition, expression levels of stromal HAS1 and HAS2 were related to obesity, large tumor size, lymph node positivity, and estrogen receptor negativity. Thus, stromal HAS1 and HAS3 were independent prognostic factors in the multivariate analysis. The data suggest that increased levels of HAS enzymes contribute to the accumulation of HA in breast cancer, and that HA is synthesized in carcinoma cells and stromal cells. The study also indicates that HAS enzyme levels are related to tumor aggressiveness and poor patient outcome representing potential targets for therapy.

Previous in vitro studies have suggested interactions between hyaluronan (HA), CD44 and HER2. We have studied the expression of HA and CD44 in a material of 278 breast cancer cases, half of which were HER2-positive. Intense stromal HA staining was associated with HER2 positivity, large tumor size, lymph node positivity, hormone receptor negativity, poor differentiation, a high body mass index, increased relapse rate and shortened overall survival. Among the 139 HER2-positive cases, the relapse rate was associated with the intensity of stromal HA staining as most of the relapses occurred in the cases with intense stromal HA staining. The presence of HA in the carcinoma cells was related to the frequency of relapses as none of the patients without HA in carcinoma cells experienced a relapse, whereas 33.3% of those with a high percentage of HA-positive carcinoma cells suffered a relapse. CD44 positivity in carcinoma cells was related to poor differentiation, postmenopausal status and triple negative breast carcinoma. CD44 positivity in stromal cells was associated with HER2 positivity, large tumor size, hormone receptor negativity, poor differentiation, increased relapse rate and shortened overall survival. The association between HER2 positivity and intense stromal HA staining indicates that HA could be one of the factors involved in the unfavorable outcome of HER2-positive patients. This study also suggests that HA in breast carcinoma cells and CD44 in stromal cells may have clinical significance.Hyaluronan (HA) is one of the main components of the extracellular matrix, and its concentration is high especially during fetal development and wound healing. 1,2 The amount of HA is also high in many tumors where HA abundance is associated with aggressive tumor type and cancer progression. 1-4 HA is synthesized by HA synthases (HAS1-3) at the intracellular face of the plasma membrane and extruded to the cell surface and pericellular and extracellular matrices. 5 Tumor HA has been associated with epithelial-mesenchymal transition (EMT), 6 multidrug resistance, 7 host-tumor interactions 8 and angiogenesis. [9][10][11] These diverse effects of HA may be due to its physical properties, that is, making the environment more favorable for cell movement, or to specific signals mediated either by its own receptors CD44 and the receptor for hyaluronan mediated motility (RHAMM), or by modifying the responses of growth factor receptors. 6,12 CD44 is a transmembrane receptor protein that participates in many cell-cell and cell-matrix interactions. 13,14 The role of CD44 in cancer is complex because alternative splicing of its mRNA leads to production of several CD44 variants. 14,15 Conflicting results have been published on the contribution of CD44 to the progression of human breast cancer. 16,17 CD44 is the principal cell surface receptor for HA, and the interactions between HA and CD44 can activate a large number of intracellular signaling pathways. 7,18,19 Post-translational modifications of CD44 influence its binding to HA and ...