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**22** 

*Kuwait* 

**Endocrine Resistance and Epithelial** 

Sanaa Al Saleh and Yunus A. Luqmani *Faculty of Pharmacy, Kuwait University* 

**Mesenchymal Transition in Breast Cancer** 

Estrogen plays a major part in the regulation of cell proliferation and survival, controlling female physiology, reproduction and behaviour (Musgrove and Sutherland, 2009). It however assumes a more malevolent role in its association with breast cancer pathogenesis. Consequently, therapies have been designed to block the actions of estrogen mediated through its receptors (ERα and ERβ), or to simply reduce its levels in the body (Zilli et al., 2009). Since Beatson (1896) first introduced ovariectomy over a century ago as the first therapeutic modality to reduce the adverse effects of estrogen, endocrine therapy has developed into the cornerstone of breast cancer treatment for those 60-70% of patients whose tumours over-express ER and/or progesterone receptor (PR) (Massarweh and Schiff, 2007; Zilli et al., 2009). For three decades, selective estrogen receptor modulators (SERMS), predominantly tamoxifen, have proved to be effective agents for the suppression of breast cancer growth in both early and advanced disease (Normanno et al., 2005). Tamoxifen has significantly improved the quality of life and survival of many patients with metastatic disease, as well as displaying prophylactic benefit, particularly in women with ductal

However, about half of ER+ patients with advanced disease and nearly all patients with metastatic disease fail to respond to first-line tamoxifen therapy. About 40% of patients receiving tamoxifen as adjuvant therapy experience tumour relapse and die from their disease, and a third of women treated with tamoxifen for 5 years develop recurrent disease within 15 years (Normanno et al., 2005). The introduction of pure estrogen antagonists such as fulvestrant, to overcome the apparent disadvantage of tamoxifen with its partial agonist properties, did not resolve the resistance problem (Osborne and Schiff, 2011). Second line therapy with other endocrine agents designed to inhibit peripheral extra-gonadal synthesis of estrogen in postmenopausal women produces some beneficial effects but for the most part serves merely to delay onset of endocrine resistance (Massarweh and Schiff, 2007). This refractiveness to continued administration of anti-estrogens and aromatase inhibitors poses a significant therapeutic problem that has been addressed by a large number of studies. Several theories have been proposed to explain this phenomenon, based on observations made with a variety of *in vitro* cellular models (Normanno et al., 2005). The consensus opinion seems to be that whereas *de novo* resistance is most likely due to low levels of ER expression, *acquired* resistance is predominantly the consequence of an attenuated response to other peptide growth factors that normally play a subsidiary role in cell proliferation.

**1. Introduction** 

carcinoma-*in situ* (Fisher et al., 1999).

protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1. *Proc Natl Acad Sci U S A,* Vol. 96, No. 6, pp, 3071-3076.

