A putative role for psoriasin in breast tumor progression

• Psoriasin (S100A7) was identifi;ed as a gene highly expressed in psoriatic keratinocytes and highly and more frequently expressed in ductal carcinoma in situ (DCIS) than in invasive breast carcinomas (IBC), suggesting a potential role in tumor progression. Psoriasin expression is associated with poor prognostic factors in both DCIS and IBC. Several putative functions have been proposed for psoriasin in various disease types, but none of these can fully explain its involvement in breast tumor progression. Here, we show that down-regulation of endogenous psoriasin expression via stable short hairpin RNAs in a human IBC cell line (MDA-MB-468) increases cell migration and invasion without influencing cell proliferation and survival in vitro but inhibits tumor growth in vivo. These seemingly paradoxical results are potentially explained by the dramatic up-regulation and down-regulation of matrix metalloproteinase-13 and vascular endothelial growth factor (VEGF), respectively, observed in cells with decreased psoriasin levels compared with controls. Correlating with this, high psoriasin expression in human IBC is associated with increased angiogenesis and worse clinical outcome, and psoriasin mRNA levels are coordinately regulated with VEGF and other genes related to hypoxia and mitochondrial reactive oxygen species (ROS). Based on these results, we propose that psoriasin may play a role in breast tumor progression by promoting angiogenesis and enhancing the selection for cells that overcome its anti-invasive function. This hypothesis may explain why psoriasin expression is highest in high-grade and/or estrogen receptor-negative tumors, as these are associated with increased hypoxia and ROS, a setting in which the angiogenic effects of psoriasin are most important.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Dermatologi och venereologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Dermatology and Venereal Diseases (hsv//eng)

Keyword

Animals

Apoptosis

Breast Neoplasms/blood supply/*metabolism/pathology

Calcium-Binding Proteins/*physiology

Carcinoma

Intraductal

Noninfiltrating/blood supply/metabolism/pathology

Collagenases/metabolism

Disease Progression

Down-Regulation

Female

Humans

Matrix Metalloproteinase 13

Mice

Mice

Nude

Neovascularization

Pathologic/*metabolism

RNA

Messenger/genetics/metabolism

RNA

Small Interfering/genetics

Receptors

Estrogen/metabolism

Tumor Cells

Cultured

Tumor Markers

Biological/physiology

Vascular Endothelial Growth Factor A/*metabolism

Publication and Content Type

ref (subject category)

art (subject category)