Oxalate Microcalcifications Induce Breast Cancer Tumors

ANDRES CASTELLARO, HUGO CEJAS, BEATRIZ L. CAPUTTO, OSCAR PUCCI AND GERMAN A. GIL

San Antonio

Simposio; SABCS; 2013

Oxalate Microcalcifications Induce Breast Cancer Tumors. One shared characteristic of breast cancer is the appearance of mammographic mammary microcalcifications. These microcalcifications are routinely used to detect breast cancer in its early stages, which is of key importance due to the possibility that early detection gives for the application of more conservative therapies and for a better patient outcome. Mammary microcalcifications can be distinguished by their physical and chemical properties, which has led to their classification at a molecular level: type I calcifications are composed of calcium oxalate while type II calcifications are composed of calcium phosphate. Oxalate (OX) is an organic dicarboxylate and may be present as free oxalic acid (OXA), as soluble salts like sodium or potassium oxalate or as insoluble calcium oxalate crystals. OX accumulation was thought to be toxic to living tissues because induces some pathological conditions. The mechanism by which mammary microcalcifications are formed is still largely unknown. No clear demonstration has shown if an active cellular process produces them or if microcalcifications are a sign of cellular degeneration. OX is produced by many kinds of cells, including apocrine cells, kidney cells and liver cells and among others. Exposure of renal epithelial cells to OX results in a diverse events that include, among others, induction of immediate early gene expression (IEG?s), re-initiation of DNA synthesis, cell growth, and more than 1000 genes up and down-regulated. Not enough research has been carried out directed to investigate the impact of the presence of OX has within the breast tumor microenvironment. Neither is it well understood, the interactions between OX breast-epithelial cells nor the signal transduction pathways involved. Herein, we have obtained enough evidence that lead us to confirm that OX excreted from apocrine cells induce alterations in normal breast epithelial cells, and that exposure of breast epithelial cells to excreted OX in a chronic way sets the stage for transformation from normal to fully developed breast tumors. We found OX-induction of DNA synthesis and IEG overexpression in Human Breast Cancer cells in culture. Moreover, by Western Blot c-Fos and Fra were overexpressed in OX treated-breast cancer cells. Additionally high correlated, OX concentration and over expression of the Immediate Early Genes c-Fos and Fra has been found in human breast cancer tumors. Tumor tissues were likened with paired adjacent non-tumor tissues and they have neither, high level of OXA nor c-Fos/ Fra over expression. Furthermore, female mice were injected into mammary fatpads with OXA and with saline solution as control. Surprisingly, mice that received OX injection generated very aggressive tumors. IEG?s were found overexpressed in these tumors. OX concentrations were analogous to human breast tumors and it was almost undetectable in the control tissues. All breast tumors were palpable within four months in 18/20 of OX treated, compared with 0/20 controls. The median survival was of 62 days (Control: undefined days; p values: <0,0001). The oxalate-breast induced tumors were very invasive, and it was possible to appreciate high rate of atypical mitosis, big pleomorphic nuclei, and macro and multi nucleoli. We conclude if we can control OXALATES production or even better their action, we can reduce significantly breast cancer tumors.