The kinome associated with estrogen receptor-positive status in human breast cancer

Abstract

Estrogen receptor alpha (ERa) regulates and is regulated by kinases involved in several functions associated with the hallmarks of cancer. The following literature review strongly suggests that distinct kinomes exist for ERa-positive and -negative human breast cancers. Importantly, consistent with the known heterogeneity of ERa-positive cancers, different subgroups exist, which can be defined by different kinome signatures, which in turn are correlated with clinical outcome. Strong evidence supports the interplay of kinase networks, suggesting that targeting a single node may not be sufficient to inhibit the network. Therefore, identifying the important hubs/nodes associated with each clinically relevant kinome in ERC tumors could offer the ability to implement the best therapy options at diagnosis, either endocrine therapy alone or together with other targeted therapies, for improved overall outcome.

Dissecting the 17β‐estradiol pathways necessary for neuroglobin anti‐apoptotic activity in breast cancer

“…On the other hand, the overexpression of human epidermal growth factor receptor 2 (HER2) is considered as an indicator of a poor prognosis (Rakha, Reis‐Filho, & Ellis, ; Valentin, da Silva, Privat, Alaoui‐Jamali, & Bignon, ; Vici et al, ; Vuong et al, ). Although the inclusion of these three breast cancer biomarkers helped to partially solve the therapeutic approach to the heterogeneity of this cancer, the existence of the endocrine therapy resistance in ERα positive breast cancer (Bruce, McAllister, & Murphy, ; Murphy, Seekallu, & Watson, ) further complicate this scenario. A step forward the improvement of ERα positive breast tumor treatment could derive from the knowledge of the E2/ERα molecular mechanisms that drive cancer cell to the survival and stress adaptation.…”

Structural and Molecular Mechanisms of Cytokine-Mediated Endocrine Resistance in Human Breast Cancer Cells

“…ERα can be activated through ligand binding to the LBD or through kinase-dependent phosphorylation in multiple domains (Bruce et al, 2014). Upon activation, ERα recruits transcriptional co-activators and corepressors, components of the basal transcriptional machinery, and the RNA polymerase II complex to regulatory regions of target genes (Métivier et al, 2003).…”

Protein Kinase Targets in Breast Cancer

“…For these reasons, luminal-A and luminal-B breast carcinomas are, theoretically, sensitive to hormone-targeted treatments. Indeed, endocrine therapy has a proven effectiveness of approximately 50–60% [ 36 , 41 ], being Tamoxifen (TMX, Nolvadex) the most common drug used in clinical practice over the past decades as first-line treatment in pre- and post-menopausal women with ER-positive breast cancer [ 42 ]. However, although this competitive ER-receptor antagonist has shown a significant reduction of recurrence (40–50%), and the risk of death from breast cancer (30–35%) [ 36 ], the existence of an important number of cases with natural or acquired resistance to tamoxifen along with long-term toxicities [ 39 ] has motivated the search for new approaches for HER2-enriched breast cancer patients ( Table 3 ).…”

“…Studies carried out in this area show an association between ER-α expression and the activity of several kinases and phosphatases [ 37 , 38 , 46 , 47 , 48 ]. Many protein kinase-encoding genes also appear to be altered in ER-positive breast tumors [ 41 , 49 ], which has opened the possibility of developing treatment strategies for these tumors that are based on the targeted inhibition of altered kinases.…”

“…The characterization of each breast cancer subtype has usually been associated to the identification of mutated or altered kinases [ 41 ]. Indeed, as each breast cancer subtype can present a unique expression profile of protein kinases that can be targeted by small molecule kinase inhibitors [ 20 , 49 ], the way to address each type of breast tumor must be different, therefore becoming necessary to carry out a previous study of each patient in order to choose the most appropriate treatment.…”