Suppression of Tumorigenicity in Breast Cancer Cells by the Microfilament Protein Profilin 1

Abstract

Differential display screening was used to reveal differential gene expression between the tumorigenic breast cancer cell line CAL51 and nontumorigenic microcell hybrids obtained after transfer of human chromosome 17 into CAL51. The human profilin 1 (PFN1) gene was found overexpressed in the microcell hybrid clones compared with the parental line, which displayed a low profilin 1 level. A comparison between several different tumorigenic breast cancer cell lines with nontumorigenic lines showed consistently lower profilin 1 levels in the tumor cells. Transfection of PFN1 cDNA into CAL51 cells raised the profilin 1 level, had a prominent effect on cell growth, cytoskeletal organization and spreading, and suppressed tumorigenicity of the stable, PFN1-overexpressing cell clones in nude mice. Immunohistochemical analysis revealed intermediate and low levels of profilin 1 in different human breast cancers. These results suggest profilin 1 as a suppressor of the tumorigenic phenotype of breast cancer cells.

Profilin-1 is a negative regulator of mammary carcinoma aggressiveness

“…Third, the present study is the first demonstration of the in vivo effect of Pfn1 overexpression on breast cancer cells in an orthotopic setting. Our finding that Pfn1 overexpression suppresses orthotopic tumorigenicity of MDA-MB-231 cells reproduces previous results reported for another breast cancer cell line in subcutaneous xenograft models (Janke et al, 2000;Wittenmayer et al, 2004), and thus provides a further supportive evidence for the tumour-suppressive property of Pfn1 in breast cancer.…”

“…Similar to previous observation of Pfn1 downregulation in human breast cancer tissue and a wide range of other breast carcinoma cell lines (Janke et al, 2000), we observed that MDA-MB-231, our model breast cancer cell line, also expresses significantly less Pfn1 compared to normal HMEC ( Figure 1A). Because of a general theme of Pfn1 downregulation in many different breast cancer cell lines, we specifically hypothesised that downregulation of Pfn1 expression confers increasing aggressiveness to both normal HMEC and breast cancer cells.…”

“…In vivo effect of Pfn1 overexpression on mammary tumour cells has been examined for only one cell line (CAL51) so far where suppression of tumorigenicity was observed (Janke et al, 2000;Wittenmayer et al, 2004). However, these studies were performed in a non-orthotopic model system.…”

“…Experimental manipulations restoring the normal expression levels of several different types of ABPs have been successful in suppressing the phenotype of transformed cells (Gluck et al, 1993;Tanaka et al, 1995;Nikolopoulos et al, 2000), therefore implying that deregulation of ABPs directly contribute to oncogene-induced transformed phenotype of tumour cells. In the emerging story on the role of ABPs in cancer, profilin-1 (Pfn1 -a ubiquitously expressed G-actin-binding protein) is found to be expressed at a significantly low level in both human breast cancer tissue and a variety of breast carcinoma cell lines (Janke et al, 2000), pancreatic (Gronborg et al, 2006) and hepatic (Wu et al, 2006) carcinoma cells compared to their normal counterparts. These interesting observations appear to suggest that loss of Pfn1 expression may have a general relevance in cancer progression.…”

“…These interesting observations appear to suggest that loss of Pfn1 expression may have a general relevance in cancer progression. Pfn1-overexpressing CAL51 breast cancer cells failed to form tumours when xenografted subcutaneously in nude mice, which suggested that Pfn1 could also be a tumour-suppressor protein (Janke et al, 2000;Wittenmayer et al, 2004). Whether overexpression of Pfn1-elicits similar tumour-suppressive effect at the orthotopic site is not known.…”