**7. P-glycoproteins and breast cancer resistance protein (Bcrp)**

P-glycoproteins and breast cancer resistance protein (Bcrp) also play important roles in resistance and therapeutic outcome of breast cancer therapy and mutations in MDR genes (which codes pglycoproteines) and influence the risk and resistance to treatment. Many drugs are substrates for this transporters and the reduction in their access to tissues can result in increase in metastasis and drug resistance. From glycoprotein family, glycoprotein non-metastatic B (GPNMB, also named as Osteoactivin) enhances breast cancer metastasis in an *in vivo* mouse model. It also has been studied as a prognostic indicator of recurrence. The data suggested this glycoprotein as a novel therapeutic target in breast cancer. GPNMB usually express in basal/triple-negative subtype of breast cancer and is associated with poor outcome (35).

Fetuin-A is another glycoprotein which its role in mammary tumorigenesis has been studied.

It is a serum component protein which forms approximately 45% of non-collagenous glycoproteins which is synthesized by the liver and excreted into plasma. It is a conserved member of the cysteine protease inhibitors which contains the TGF-β receptor II homology 1 domain (TRH1). As a result, it is able to compete with epithelial cells for TGF- β. The possible sequestration of TGF β by fetuin-A could affect TGF β signaling in breast epithelial cells as previously reported for intestinal epithelial cells. Fetuin-A shows reduced incidence of mammary tumors for breast cancer by more than 60% and increases tumor onset. Another tumor-enhancer property of fetuin-A is its stabilizer effect matrix metalloproteinases in the extracellular matrix.

Consequently, they can drive the "tumor islands" to invade the stroma metastasize to other organs. Stronger TGF-ß signaling in the absence of fetuin-A exert suppressor effect on cell proliferation through increase in is ARF-p53 expression, whereas the sequestration of TGF-ß by fetuin-A, results in reduction of its signaling in epithelial cells and inactivation of ARFp53 which is parallel with shortening the latency of mammary tumorigenesis and implications of breast cancer development (36).
