**3.1 E2 and P4 in breast cancer development**

Broad spectrum of physiological activity of steroid hormones displays its dark side in cases when cells in steroid hormone guided organs lose their normal responsiveness to hormone.

eutopic and ectopic endometrial tissues expresses ERs and PRs and they respond to ovarian steroid hormones but the predominance of ERα and PRA receptors have been described in cases of ectopic lesions (Matsuzaki et al., 2001; Attia et al., 2000). Despite the obvious importance of E2/P4 in the development of the endometriosis, the exact aetiology and pathogenesis of it are still unclear. It is predicted that in general endometriosis could affect about 10% of women of reproductive age and up to 25-50% of women seeking infertility treatment. There is still uncertainty whether the decreased fertility is related to reduction of the oocyte/embryo quality or dysregulation of the endometrium (Kim et al., 2007). Aberrant gene expression in endometrium which is suboptimal for implanting blastocyst has been shown by several studies in cases of endometriosis (Giudice et al., 2002; Kao et al., 2003). Even though endometriosis has been characterized as E2-dependent gynaecological disease, where E2 favours the growth of the tissue, the dysregulation of the P4 response on the molecular level is suggested in endometriosis. It has been noticed that endometriotic tissue does not respond to P4 as normal endometrium does. Altered PR expression or diminished activity predictably results in differential gene expression compared to eutopic tissue (Cakmak et al., 2010). For example, altered P4 signalling can cause unpaired regulation of *HOXA 11, HOXA12* genes in ectopic tissue which are expressed in high levels during the IW in normal tissue (Cakmak et al., 2010). The up-regulation of *HOXA10* and *HOXA11*  expression fails to occur in women with endometriosis (Taylor et al., 1999). Recent studies looking for functional miRNA-s have shown up-regulation of miR-21 in eutopic endometrium of women with versus without endometriosis (Luo et al., 2010; Aghajanova et

Hopefully further studies in the future help us understand the molecular mechanisms,

The development and physiology of human mammary gland is also under the strict control of steroid hormones, including E2 and P4. The mammary gland is not completely formed at birth, but begins to develop in early puberty when the primitive ductal structures enlarge and branch (Russo et al., 1987). From that point ovarian E2 and P4 are fundamental for the growth and differentiation of the duct system. There are slight cyclical changes during each menstrual cycle caused by ovarian steroid hormones where E2 is increasing the volume of the tissue and P4 is responsible of the acinar growth of breast tissue. During pregnancy, the mammary gland epithelium experiences its greatest and most rapid proliferation initially as a response to the hormones produced by corpus luteum, following by placental hormones. Due to difficulties in studying developing mammary gland there is relatively small amount of information about normal ER and PR expression in breast tissue. It has been confirmed that PRs and ERs are found in a minority population (7–10%) of luminal, non-dividing epithelial cells. As E2 is required to induce progesterone receptor (PR) expression it is difficult to separate the effects of P4 alone from E2. However, the obligate role of the ERs and PRs in mammary gland development has been confirmed with knocked out mice

Broad spectrum of physiological activity of steroid hormones displays its dark side in cases when cells in steroid hormone guided organs lose their normal responsiveness to hormone.

which are responsible for the development of endometriosis.

studies (Bocchinfuso and Korach, 1997; Humphreys et al., 1997).

**3.1 E2 and P4 in breast cancer development** 

**3. The role of E2 and P4 in mammary gland**

al., 2011).

Third of female malignancies are hormone dependent in their growth. Most prominent leading death causing factors for women under age of 50 are breast cancer and also various cancers of reproductive system. Many factors are involved in the development of breast cancer, including genetics, lifestyle, diet, endogenous hormone status and environment. Demographic risk factors for breast cancer are early age of menarche, nulliparity, late fullterm pregnancy, higher social class and increasing age. Known factors with protective effects on breast cancer development are early full-term pregnancy, increasing number of births, longer periods of anovulation and more physical activity (Bernstein et al., 1994). The incidence of this lethal cancer has steadily increased during the last centuries in part due to the better and more widespread screening procedures. Increased ERα expression is one of the earliest changes occurring in the tumorigenic process and is associated with uncontrolled proliferation of the breast tissue (Khan et al., 1994). Some data is showing that ERβ could negatively modulate the effects of ERα but the prognosis for endocrine therapy are still under the question because of the somehow contradictory outcomes (Roger et al., 2001; Speirs et al., 2002). Similarly PR isoform ratio also seems to have a role in breast tumorigenesis as the ration of PRA and PRB has been altered with PRA prevalence (Mote et al., 2002).

Currently, only the expression level of ERα is measured for clinical decision-making and treatment of breast cancer patients as a favourable prognosis in primary tumours. Still, only 50% of ERα-positive tumours respond well to hormonal therapy. Large research programs are dedicated to search for better and more specific clinical breast cancer markers. The significance of ERβ status is still controversial and further analysis of the role it plays in the pathogenesis of breast cancer is required. As more experimental information on E2 mediated signalling accumulates, new possibilities emerge for breast cancer therapy.
