Placental isoferritin associated p43 antigen correlates with features of high differentiation in breast cancer

Abstract

Placental isoferritin (PLF), an acidic isoform of ferritin, and its unique superheavy chain p43 have been recently described to be synthesized by breast cancer cell lines but not by normal breast epithelial cells. Since previous reports have demonstrated a correlation between the content of 'normal' ferritin in breast cancer tissue, degree of differentiation, and prognosis, we have tried to evaluate the correlation of p43 in the cytosol of 122 breast cancer samples with commonly applied prognostic factors and features of proliferation and differentiation. In parallel, we investigated the correlation of p43 expression in MCF-7 and T47-D breast cancer cell lines during proliferation induced by estradiol plus fetal calf serum (assessed by 3H-thymidine incorporation), compared to p43 expression in stationary non-stimulated cell cultures. The levels of p43 in breast cancer cytosols correlated significantly negatively with tumor size (p = 0.0001), histologic grading (p = 0.0038), nuclear pleomorphism (p = 0.0019), rate of mitosis (p = 0.0002), and lymphocytic reaction (p = 0.0001), and significantly directly with the estrogen receptor status (p = 0.0009). Although patients with a higher p43 content showed a trend for a better outcome (median follow-up: 61.4 months), an independent influence of the cytosolic p43 content on survival could not be confirmed by a multivariate Cox model. In accordance with the observed negative correlation of features of differentiation vs. p43 expression, induction of proliferation by estradiol plus FCS added to serum-free tissue culture medium correlated with a decrease of p43 synthesis in both cell lines. Expression of p43 in estrogen and FCS-absent media revealed also a decrease in relation to a low spontaneous proliferation. However, the drop of p43 synthesis was significantly stronger in cell lines with estrogen-stimulated proliferation. Our in vitro and cytosol results confirm recent clinical observations describing an inverse correlation of p43 synthesis with the degree of proliferation and differentiation in breast cancer. However, the pathologic mechanisms leading to this phenomenon as well as the negative correlation with lymphocytic infiltration are still unclear and need to be further elucidated.

Immunosuppression by breast cancer associated p43-effect of immunomodulators

“…The lymphocyte activation by IL-2 and its inhibition by p43 was exhibited mainly in patients with early breast cancer (tumors smaller 2 cm, node negative, GI). This correlates with previous demonstrations of an expanded population of p43 positive lymphocytes in the circulation of patients with early breast cancer and their diminution in advanced disease [5,17].…”

“…This leads us to suggest that T cells expressing a receptor for p43 are activated at the earliest stages of breast cancer. However, their proliferation is inhibited by the surface bound p43 derived from the primary breast tumor [17]. This inhibition may affect the further differentiation of effector cells which influence other cells of the immune system involved in tumoricidal function [19][20][21].…”

“…In case of cancer, surgical removal of the axillary lymph node compartments I and II was mandatory. The median number of lymph modes removed in cancer patients was 13 [10][11][12][13][14][15][16][17]. Histologic grading of malignant tumors was performed according to Bloom and Richardson [9], and the estrogen receptor content was determined by the immunohistochemical (ICA) method previously published [10].…”

Identification of women with early breast cancer by analysis of p43-positive lymphocytes

“…False negative p43 values were explained by the presence of highly undifferentiated (grade III) tumours and by lymph node metastases. Likewise, in 122 patients with breast cancer, the expression of p43 was significantly higher in tumour cytosols with grade I or low-grade nuclear pleomorphism than in grade III tumours (Rosen et al, 1992).…”

“…This isoferritin has been shown to mediate immunosuppression during pregnancy (Sirota et al, 1989;Maymon and Moroz, 1996). Moreover, an elevated p43 level has been observed in the peripheral blood of patients with Hodgkin's disease, AIDS and breast cancer (Moroz et al, 1977Rosen et al, 1992). In an investigation by Moroz involving more than 3000 women, 80% of stage I and II breast cancer patients, but less than 10% of women with benign breast disease or healthy controls, had increased p43 expression on lymphocytes, as determined by radioimmunoassay .…”