**6. Breast cancer stem cells**

Recently, cancer stem cells (CSCs) have attracted a lot of attentions and some roles have been determined for estrogen and progesterone by affecting these cells. It has become clear that the normal and malignant breast contains stem cells (SCs) that play an essential role in the normal development o f the breast and are likely to play a significant role in the genesis and growth of human breast cancer. The CSC hypothesis introduced tissuespecific Stem Cells (SCs) and/or their early progenitors as the main causes of the malignant behavior of cancer. These cells are undifferentiated and, as a result, have the ability to divide into two daughter cells. But, division is asymmetrical and will cause an identical clone of the mother cell and another cell which can divide and fully differentiate into new cell line. This latter daughter cell is named a Progenitor. Physiological functions of breast SCs include producing the early milk ducts and the surrounding stroma at puberty and repair of damaged tissue and renovation the lost ductal and stromal cells during adult life.

Breast Cancer from Molecular Point of View: Pathogenesis and Biomarkers 113

Progestins, on the other way, are able to upregulate growth factor and cytokine receptors at the cell surface. They are also involved in regulation of several intracellular effectors including Stat 5, and by potentiating mitogen-activated protein kinase (MAPK) and Janus kinase activities by increasing the levels and altering the subcellular compartmentalization of them at cytoplasmic level. Furthermore, growth factor-regulated nuclear transcription factors may have synergistic effect with PRs' agonists to regulate the function of key genes

Recently, the influence of estrogen, progesterone, and progestins on breast CSCs and their progeny has been found out. As it has been demonstrated in figure 3, although most of breast CSCs are estrogen receptor negative and progesterone receptor negative, some intermediate progenitor forms own hormone receptors, especially progesterone receptor. Progesterone and progestin specially work on these breast cancer stem intermediate forms, inducing them to return back to a more primitive breast CSC forms, thus increasing the pool of malignant SCs (29). These cells escape the microenvironment control. Estrogens, on the other hand, induce the proliferation of these abnormal progenitors, resulting in breast

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

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

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

Some newly reported show that elevation in expression level of astrocyte elevated gene-1(AEG-1, also known as Metadherin and lyric) in human breast cancer dramatically

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

subtype of breast cancer and is associated with poor outcome (35).

which are involved in breast cancer. (34)

tumor. Figure 3 summarize this hypothesis.

metalloproteinases in the extracellular matrix.

implications of breast cancer development (36).

**7.1 Astrocyte Elevated Gene-1** 

In contrast to their progenitor and differentiated offspring, breast SCs are very long life and thus influences of the effect of chemicals and radiation. Since breast CSCs escape from the control of surrounding microenvironment, they are able to bear malignant progenitor offspring. The result will be the production of malignant daughter cells that create the bulk of the tumor.

As a rare phenomenon, some of breast CSCs are quiescent and, as it is expected, will be spared by current cancer therapies whose targets are rapidly divided cells (29-32)
