**3. Fb-3 action mechanism**

Fb-3 interacts with other base membrane proteins, such as extracellular matrix 1 protein (ECM1), the tissue inhibitor of metalloproteinase-3 (TIMP-3), endostatine (20 kDa C-terminal fragment of collagene XVIII), B hepatitis virus antigene X, tropoelastine (elastine monomeric subunit), etc. These interactions are likely to contribute to maintaining the base membrane integrity and anchoring other ECM structures, e.g., elastic fibers [17].

Fb-3 stimulates TIMP-1 and TIMP-3 expressions, but it inhibits expression and activities of (MMP)-2, MMP-3 and MMP-9 matrix metalloproteinases. It is associated with thinner elastic fibers, whereas it is not found in bigger elastic structures such as the aortic elastic lamina. Experimental studies have highlighted that EFEMp1 *knockout* rats show an early aging process and develop multiple tissue hernias, among which inguinal hernias, pelvic prolapse, and xiphoid process protrusions. In these guinea pigs, small-size elastic fibers of the connective tissue, including those of small blood vessel adventitia and vaginal tunics, are reduced both in size and resistance. A disgregation or a reduction of the elastic fibers in such tissues is probably responsible for phenotypes suffering from early aging and multiple hernias observed in *knockout* rats for EFEMP1.

Besides its role in maintaining ECM, Fb-3 also seems to have signaling functions. Indeed, Fb-3, by interacting with DA41, a protein, which binds the onco-suppressor DAN gene, can trigger DNA synthesis. The expression of EFEMP1 is thought to have a role in cell proliferation and tissue growth processes [18].

Inactivation of EFEMP1, through promoter methylation methylation of the stimulator, is associated with lung and breast cancers. EFEMP1 undergoes a *down-regulation* in 60% of breast cancer cases and the promoter methylation methylation of the stimulator just seems to be the main reason for this reduced expression. Analysis of

primary primitive, clinically well-characterized breast cancers has revealed a significant correlation between a reduced EFEMP1 expression and a reduction of the time span free from illness and of survival, generally. In the light of this evidence, one can assume that EFEMP1 might be used as molecular marker in lung and breast cancers.

An alteration of Fb-3, as an element of the base membrane, would seem to play an important role in tumor metastatic phenomena. Fb-3 would also seem to have a triggering action in cellular proliferation and migration processes. However, both the pathophysiological role of Fb-3 in base membranes and how the alteration and/ or function failure of this protein may/may not have a part in causing pathologies are still to be ascertained.
