Abstract
The importance and role of the estrogen receptor (ER) pathway has been well-documented in both breast cancer (BC) development and progression. The treatment of choice in women with metastatic breast cancer (MBC) is classically divided into a variety of endocrine therapies, 3 of the most common being: selective estrogen receptor modulators (SERM), aromatase inhibitors (AI) and selective estrogen receptor down-regulators (SERD). In a proportion of patients, resistance develops to endocrine therapy due to a sophisticated and at times redundant interference, at the molecular level between the ER and growth factor. The progression to endocrine resistance is considered to be a gradual, step-wise process. Several mechanisms have been proposed but thus far none of them can be defined as the complete explanation behind the phenomenon of endocrine resistance. Although multiple cellular, molecular and immune mechanisms have been and are being extensively studied, their individual roles are often poorly understood. In this review, we summarize current progress in our understanding of ER biology and the molecular mechanisms that predispose and determine endocrine resistance in breast cancer patients.
Highlights
The complex association of endocrine ablation and breast cancer (BC) was discovered in 1896 when Beatson revealed that oophorectomy on an advanced cancer patient led to a pronounced and marked response [1]
This study demonstrated that triple blockade with RAD001, neratinib and tamoxifen/fulvestrant was highly effective in the long term E2 deprived BC cell lines and was well-tolerated in a xenograft model [272]
Yamashita et al in 2006 had shown that STAT5 is a strong prognostic molecular marker in estrogen receptor (ER)+ BC. They investigated the expression of STAT3 and STAT5 in more than 500 BC tissues by immunohistochemical techniques and observed that in ER+ patients with STAT5 positive tumors there was significantly increased overall survival, thereby suggesting that expression of STAT5 is helpful in selecting patients who could possibly benefit from endocrine therapy [336]
Summary
The complex association of endocrine ablation and breast cancer (BC) was discovered in 1896 when Beatson revealed that oophorectomy on an advanced cancer patient led to a pronounced and marked response [1]. An in-depth characterization of tumors through large integrated genomic landscape studies on metastatic breast cancer (MBC) patients has provided valuable insights into a few of the genomic drivers, the role of heterogenic genomic architecture of cells within the tumor, the cellular and molecular determinants that define response to endocrine therapy along with identified novel biomarkers and therapies [9, 21, 22]. These studies have demonstrated a central clonal hub at the primary tumor site and acquired mutations and drivers that promotes metastasis [21]. This review discusses in detail the various intricate and sophisticated web of pathways involved in ER signaling and highlights schemes for treatment
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