Elevated expression and altered processing of fibulin-1 protein in human breast cancer

Abstract

The extracellular matrix protein fibulin-1 suppresses the motility and invasiveness of a variety of tumour cell types in vitro as well as the growth of fibrosarcoma tumours in nude mice. In this study, fibulin-1 protein expression in breast carcinoma specimens and normal breast tissue was evaluated immunohistologically. Fibulin-1 protein expression was also semiquantitatively assessed by immunoblot analysis in a collection of normal breast tissues (n ¼ 18), benign tumours (n ¼ 5) and breast carcinomas (n ¼ 39). In normal breast tissue, fibulin-1 protein expression predominated in the ductal epithelium and underlying myoepithelium, with weaker staining evident in the loose connective surrounding the ducts. Examination of breast carcinomas revealed that the tumour cells also expressed fibulin-1 protein. The level of mature fibulin-1 polypeptide (100 kDa) was higher in the breast carcinoma specimens as compared to normal breast tissue (Mann -Whitney U-test, P ¼ 0.0005). In addition to the mature fibulin-1 polypeptide, several smaller sized polypeptides of 55, 50 and 25 kDa were detected using monoclonal antibodies reactive towards an epitope located at the N-terminus of fibulin-1. The immunoreactive 50 kDa polypeptide was detected more frequently in breast carcinoma specimens than in normal breast tissue (w 2 ¼ 17.22, Po0.0001). Furthermore, the ratio of the 50 kDa fragment to the mature fibulin-1 polypeptide correlated with the level of oestrogen receptor a (Spearman correlation coefficient, rs ¼ 0.49, Po0.003, n ¼ 36) and progesterone receptor (rs ¼ 0.43, P ¼ 0.008, n ¼ 36) expression in the tumour specimens. Taken together, these findings indicate that elevated expression and altered processing of fibulin-1 is associated with human breast cancer.

Immunological and pathobiological roles of fibulin-1 in breast cancer

“…The two isoforms share a common 566-amino-acid N-terminal segment and differ in their C-termini. However, it (Greene et al, 2003). A further mechanism might be the imbalance in expression between Fbln-1 isoforms, a possibility supported by the finding of an increased Fbln-1C : Fbln-1D mRNA ratio observed in ovarian cancer cells compared to normal ovaries and benign tumours (Moll et al, 2002).…”

“…Several studies have implicated Fbln-1 as having a role in cancer (Qing et al, 1997;Twal et al, 2001;Du et al, 2002;Moll et al, 2002;Greene et al, 2003). An elevated expression of Fbln-1 is associated with human breast tumours (Forti et al, 2002;Greene et al, 2003).…”

“…An elevated expression of Fbln-1 is associated with human breast tumours (Forti et al, 2002;Greene et al, 2003). Fbln-1 inhibits in vitro adhesion and motility of various carcinoma cell lines (Twal et al, 2001).…”

FBLN1 (fibulin 1)

“…Its overexpression can serve as a tool for early detection of breast cancer and acts to promote breast cancer cell survival during doxorubicin treatment (Pupa et al, 2007). In a series of 36 primary breast carcinomas, the expression of mature fibulin-1 polypeptide (100 kDa) did not correlate with estrogen receptor-alpha (ERα) or progesterone receptor (PR) levels, whereas a positive correlation was found between fibulin-1 processing (50 kDa fragment) and ERα and PR protein levels (Greene et al, 2003). Castagnoli L, et al Atlas Genet Cytogenet Oncol Haematol.…”

“…Several studies have reported that fibulin-1 is overexpressed in various human neoplasias and it is implicated in processes such as invasion, motility, and in vivo tumor growth (Du et al, 2002;Greene et al, 2003;Moll et al, 2002;Qing et al, 1997;Twal et al, 2001). Fibulin-1 inhibits in vitro adhesion and motility of various carcinoma cell lines (Twal et al, 2001).…”