**6.1 Role of estrogens and progestins**

It has been suggested that hormone therapy or oral contraception may increase the risk of breast tumor development because of proliferation of existing quiescent tumor cells. The estrogen receptor-alpha (ERa) has an important role in normal breast cell development. Genetic alterations in the ER a gene locus might therefore have important effects in breast carcinogenesis. Polymorphisms can also cause even more increase in estrogen-associated breast cancer risk. At least three polymorphisms, i.e. the G478T, A908G, and C975C have been put in this category (33).

Fig. 3. Effect of Estrogens and progestines on breast CSCs. CSCs divide into abnormal offspring which can differentiate to all types of breast tumoral cells

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

As a rare phenomenon, some of breast CSCs are quiescent and, as it is expected, will be

It has been suggested that hormone therapy or oral contraception may increase the risk of breast tumor development because of proliferation of existing quiescent tumor cells. The estrogen receptor-alpha (ERa) has an important role in normal breast cell development. Genetic alterations in the ER a gene locus might therefore have important effects in breast carcinogenesis. Polymorphisms can also cause even more increase in estrogen-associated breast cancer risk. At least three polymorphisms, i.e. the G478T, A908G, and C975C have

Fig. 3. Effect of Estrogens and progestines on breast CSCs. CSCs divide into abnormal off-

spring which can differentiate to all types of breast tumoral cells

spared by current cancer therapies whose targets are rapidly divided cells (29-32)

of the tumor.

**6.1 Role of estrogens and progestins** 

been put in this category (33).

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 which are involved in breast cancer. (34)

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 tumor. Figure 3 summarize this hypothesis.
