Research Project
10228560
Non-genomic estrogen signaling has been implicated in mediating therapeutic resistance to anti-estrogen therapies in breast carcinoma (BCa) and may contribute to the mitogenic effects of selective estrogen receptor modulators (SERMS). ER?36 [a 36 Kd transcript variant of estrogen receptor alpha (ER?)] mediates non- genomic estrogen signaling, and is implicated in anti-estrogen resistance and anti-estrogen induced mitogenesis1. Dual inhibition of ER?66 (full length ER?) and ER?36 signaling might prove to be a more efficacious mode of antihormonal therapy that avoids the acquisition of anti-estrogen induced resistance and tumorigenesis. This can be achieved by pharmacological targeting of the common posttranslational regulatory mechanisms (ie, phosphorylation) between the two isoforms. CX4945 (silmitasertib), a clinical stage CK2 inhibitor, represses protein levels of both ER?66 and ER?36. As such CX4945 might serve to uniquely disrupt oncogenic kinase signaling as well as reduces stability of ER? isoforms in BCa. We hypothesize that CX4945 inhibits both genomic and nongenomic estrogenic signaling by functioning as an indirect pan-estrogen receptor downregulator which disrupts both ER?66 and ER?36 expression in BCa. In order to test this hypothesis we will: Aim I. Investigate the role of the ER?66/36 /CK2 signaling axis in the development of tamoxifen resistance. For this aim we hypothesize that CK2 promotes the development of 4HT resistance by promoting aberrant ER? signaling. We will determine the incidence and causative role of altered ER?36 and CK2 expression in the development of tamoxifen resistance in breast cancer. Aim 2 Elucidate the mechanisms of CX4945 mediated downregulation of ER?66/36 in BCa. Here we hypothesize that pharmacological inhibition of CK2 with CX4945 renders ER? isoforms susceptible to the 26S proteasomal degradation pathway. We will ascertain the impact of CK2 mediated phosphorylation of ER?66/36 on chaperone interaction, ubiquitination and subsequently the proteolytic degradation of ER?36. Aim 3 Assess the antineoplastic efficacy of CX4945 in paired patient derived xenograft (PDX) models of 4HT sensitive and resistant models of BCa. We hypothesize that CX4945 will inhibit the progression of tamoxifen-sensitive and tamoxifen-resistant (de novo and acquired) PDX tumors. PDX tumors from endocrine sensitive patients will be used to generate models of acquired resistance, whereas de-novo resistance will be modelled using PDX from patients with Y537S mutation. The successful completion of these studies could lead to the use of CX4945 or similar CK2 inhibitors with indirect pan-ER? downregulating functions in the treatment of hormone sensitive and hormone resistant breast cancer.
