Linda Snell

Psoriasin (S100A7) Expression and Invasive Breast Cancer

Alteration of psoriasin (S100A7) expression has previously been identified in association with the transition from preinvasive to invasive breast cancer. In this study we have examined persistence of psoriasin mRNA and protein expression in relation to prognostic factors in a cohort of 57 invasive breast tumors, comprising 34 invasive ductal carcinomas and 23 other invasive tumor types (lobular, mucinous, medullary, tubular). We first developed an IgY polyclonal chicken antibody and confirmed specificity for psoriasin by Western blot in transfected cells and tumors. The protein was localized by immunohistochemistry predominantly to epithelial cells, with both nuclear and cytoplasmic staining, as well as occasional stromal cells in psoriatic skin and breast tumors; however, in situ hybridization showed that psoriasin mRNA expression was restricted to epithelial cells. In breast tumors, higher levels of psoriasin measured by reverse transcriptase-polymerase chain reaction and Western blot (93% concordance) were significantly associated with estrogen and progesterone receptor-negative status (P < 0.0001, P = 0.0003), and with nodal metastasis in invasive ductal tumors (P = 0. 035), but not with tumor type or grade. Psoriasin expression also correlated with inflammatory infiltrates (all tumors excluding medullary, P = 0.0022). These results suggest that psoriasin may be a marker of aggressive behavior in invasive tumors and are consistent with a function as a chemotactic factor.

Lumican and decorin are differentially expressed in human breast carcinoma.

Previous studies have shown that lumican is expressed and increased in the stroma of breast tumours. Lumican expression has now been examined relative to other members of the small leucine‐rich proteoglycan gene family in normal and neoplastic breast tissues, to begin to determine its role in breast tumour progression. Western blot study showed that lumican protein is highly abundant relative to decorin, while biglycan and fibromodulin are only detected occasionally in breast tissues (n=15 cases). Further analysis of lumican and decorin expression performed in matched normal and tumour tissues by in situ hybridization showed that both mRNAs were expressed by similar fibroblast‐like cells adjacent to epithelium. However, lumican mRNA expression was significantly increased in tumours (n=34, p<0.0001), while decorin mRNA was decreased (p=0.0002) in neoplastic relative to adjacent normal stroma. This was accompanied by a significant increase in lumican protein (n=12, p=0.0122), but not decorin. Further evidence of altered lumican expression in breast cancer was manifested by discordance between lumican mRNA and protein localization in some regions of tumours but not in adjacent morphologically normal tissues. It is concluded that lumican is the most abundant of these proteoglycans in breast tumours and that lumican and decorin are inversely regulated in association with breast tumourigenesis. Copyright

Mammaglobin, a potential marker of breast cancer nodal metastasis

The Mammaglobin gene, a breast‐specific member of the uteroglobin gene family, has been previously identified as being overexpressed in some breast tumours, but the cellular origin and relationship to tumour progression are unknown. Using a subtractive hybridization approach, mammaglobin mRNA has also been found to be overexpressed in the in situ compared to the invasive element within an individual breast tumour. Further study by in situ hybridization performed in 13 breast tumours, selected to include normal, in situ, and invasive primary tumour elements, and in most cases axillary lymph node metastases, revealed that mammaglobin expression occurs in all elements, is restricted to epithelial cells, and is significantly increased in tumour cells compared with normal cells ( p< 0·04). Analysis of mammaglobin expression within 20 independent primary breast tumours and their corresponding axillary lymph nodes revealed that all 13 lymph nodes positive and none of the seven nodes negative for metastatic breast carcinoma by histology were mammaglobin‐positive by reverse transcription‐polymerase chain reaction (RT‐PCR) ( p=0·0001). These results suggest that mammaglobin could be a marker of axillary lymph node breast metastases. Copyright

Phospho-serine-118 estrogen receptor-alpha expression is associated with better disease outcome in women treated with tamoxifen.

Purpose: The purpose of this research was to determine whether estrogen receptor α specifically phosphorylated at Ser118 is associated with clinical outcome in primary breast tumors from estrogen receptor-positive and node-negative breast cancer patients. Experimental Design: Estrogen receptor α specifically phosphorylated at Ser118 was determined by immunohistochemistry in 117 primary breast tumors from node-negative patients who were subsequently treated with adjuvant tamoxifen. The relationship of estrogen receptor α specifically phosphorylated at Ser118 expression to disease-free survival and overall survival was determined. Results: Estrogen receptor α specifically phosphorylated at Ser118 was limited to estrogen receptor α ligand binding assay-positive tumors and among this subset was expressed in 70 (62%) of these tumors. Estrogen receptor α specifically phosphorylated at Ser118 expression was more frequently observed in progesterone receptor-positive tumors compared with progesterone receptor-negative tumors (χ2 test, P = 0.012, n = 113). A significant correlation was also seen between estrogen receptor α specifically phosphorylated at Ser118 and progesterone receptor levels (Spearman r = 0.236, P = 0.0118, n = 113). Kaplan-Meier outcome analysis showed that patients whose primary tumors expressed estrogen receptor α specifically phosphorylated at Ser118 had a longer disease-free survival (P = 0.0018, n = 113) and a trend toward better overall survival, but this was not statistically significant. Among the subset of progesterone receptor-positive tumors, progesterone receptor-positive/estrogen receptor α specifically phosphorylated at Ser118-positive patients had a significantly longer disease-free survival that progesterone receptor-positive/estrogen receptor α specifically phosphorylated at Ser118-negative patients (P = 0.0041). Conclusions: Our data suggest that estrogen receptor α specifically phosphorylated at Ser118 is a marker of a functional, intact ligand-dependent estrogen receptor signaling pathway in breast cancer and that estrogen receptor α specifically phosphorylated at Ser118 status has the potential to provide a more precise biomarker of responsiveness to endocrine therapy in conjunction with estrogen receptor α and progesterone receptor status.

Psoriasin (S100A7) expression is altered during skin tumorigenesis

BackgroundPsoriasin (S100A7) expression has previously been associated with psoriasiform hyperplasia as well as with tumor progression in breast cancer. Its expression profile for different stages of skin lesions is unknown. The aim of this study was to determine the relationship between psoriasin (S100A7) and tumor progression in skin.MethodsPsoriasin was assessed by immunohistochemistry and levels of expression determined by semi-quantitative scoring in skin biopsies from 50 patients. The cohort included normal skin, actinic keratosis, squamous carcinoma in-situ, invasive squamous cell carcinoma, and basal cell carcinoma.ResultsIn normal skin, psoriasin was rarely detected in epidermis but was expressed in underlying adnexae. In abnormal epidermis psoriasin was frequently expressed in abnormal keratinocytes in actinic keratosis, in-situ and invasive squamous cell carcinoma, but was rarely observed in the basal epidermal layer or in superficial or invasive basal cell carcinoma. The highest levels of expression were seen within squamous carcinoma in-situ. Significantly reduced levels of expression were observed in both unmatched (p = 0.0001) and matched (p < 0.004) invasive squamous cell carcinoma. Psoriasin expression within abnormal squamous lesions correlated with mitotic count (r = 0.54, p = 0.0036), however no significant relation was found with the intensity of dermal inflammatory cell infiltrates assessed within each pathology.ConclusionThese results suggest that altered psoriasin expression occurs in abnormal epidermis and that downregulation may be related to the onset of invasion in squamous cell carcinoma in skin.

S100A7 (psoriasin) expression is associated with aggressive features and alteration of Jab1 in ductal carcinoma in situ of the breast

IntroductionThe S100A7 (psoriasin) gene is highly expressed in ductal carcinoma in situ (DCIS) of the breast and can be downregulated in invasive carcinoma. Persistent S100A7 expression in invasive carcinoma is associated with a worse prognosis, and this effect may be mediated in part through interaction with the multifunctional cell signaling protein Jab1.MethodsIn order to investigate the relationship between S100A7 and progression from DCIS to invasive carcinoma, we studied S100A7 expression in 136 patients with DCIS (including 46 patients with associated invasive carcinoma) by immunohistochemistry.ResultsS100A7 expression was present in 63 out of 136 (46%) of DCIS lesions and was associated with estrogen receptor negative status (P = 0.0002), higher nuclear grade (P < 0.0001), necrosis (P < 0.0001) and inflammation (P < 0.0001). S100A7 status was no different between DCIS with and DCIS without an invasive component, but higher levels of S100A7 were present in DCIS associated with invasive carcinoma (P < 0.004). Analysis of a subset of cases showed that S100A7 expression was also associated with an increase in nuclear Jab1 (n = 43; P = 0.0019) and reduced p27kip1 (n = 47; P = 0.0168). In cases of DCIS associated with invasive carcinoma, there was also a significant reduction in S100A7 between in situ and invasive components (n = 46; P < 0.0001). In pure DCIS cases treated by local excision, there was no difference in frequency of S100A7 expression between patients with recurrence of DCIS (n = 9) and those without (n = 36).ConclusionThe findings reported here suggest that, although S100A7 may not be a marker for recurrence of DCIS, it is associated with poor prognostic markers in DCIS and may influence progression of breast carcinoma through its interaction with and influence on Jab1.

Phospho-serine-118 estrogen receptor-α detection in human breast tumors in vivo

Purpose: To determine whether estrogen receptor (ER)-α specifically phosphorylated at Ser118 is detectable in multiple human breast cancer biopsy samples. To gain insight into possible roles for P-Ser118-ERα in human breast cancer in vivo. Experimental Design: A specific antibody for P-Ser118-ERα was validated for immunohistochemistry (IHC), and Western blot analysis confirmed IHC results. IHC was used to determine the relationship of P-Ser118-ERα to known prognostic markers and active mitogen-activated protein kinase (MAPK; erk1/2) expression. Results: P-Ser118-ERα was significantly correlated with the expression of total ER, determined by ligand binding assay (r = 0.442, P = 0.002), but not with progesterone receptor expression or nodal status. P-Ser118-ERα was inversely correlated with histological grade (r = −0.34, P = 0.023), reflecting a similar trend for total ER (r = −0.287, P = 0.056). Categorical contingency analysis confirmed that P-Ser118-ERα was more frequently associated with lower than higher grade breast tumors (P = 0.038). In addition P-Ser118-ERα was significantly associated with detection of active MAPK (Erk1/2; Spearman r = 0.649, P < 0.0001; Fisher’s exact test, P = 0.0004). Conclusions: P-Ser118-ERα detection is associated with a more differentiated phenotype and other markers of good prognosis in human breast cancer. P-Ser118-ERα is correlated with active MAPK in human breast tumor biopsies, suggesting the possibility that active MAPK either directly or indirectly has a role in the regulation of P-Ser118-ERα expression in vivo. These data provide evidence for a role of P-Ser118-ERα in human breast cancer in vivo.