Many phase II and III trials are still in progress with PIK3CA-specific inhibitor to further determine the predictive therapeutic target value of mutations [155,156]. been in clinical use for decades and new classes of anti-estrogens are constantly being developed. Although a significant number of ER+ breast cancers respond to anti-estrogen therapy, 30% of these breast cancers recur, sometimes even after 20 years of initial diagnosis. Mechanism of resistance to anti-estrogens is one of the intensely studied disciplines in breast cancer. Several mechanisms have been proposed including mutations in mutations as well as crosstalk with INK 128 (MLN0128) other INK 128 (MLN0128) signaling networks lead to ligand impartial activation of ER thus rendering anti-estrogens ineffective, particularly when treatment involved anti-estrogens that do not degrade ER. As a result of these studies, several therapies that combine anti-estrogens that degrade ER with PI3K/AKT/mTOR inhibitors targeting growth factor signaling or CDK4/6 inhibitors targeting cell cycle machinery are used clinically to treat recurrent ER+ breast cancers. In this review, we discuss the nexus between ER-PI3K/AKT/mTOR pathways and how understanding of this nexus has helped to develop combination therapies. and mutations have been shown to be oncogenic mutations and important risk factors of breast cancer [33]. Other mechanisms also contribute to AKT activation. For example, EGF activation of AKT in breast cancer is usually mediated by calmodulin [34]. Furthermore, earlier studies have exhibited the importance of INK 128 (MLN0128) GTP-bound Ras-GAP in the activation of PI3K downstream of platelet-derived growth factor (PDGF) signaling, which highlights crosstalk between PI3K-AKT-mTOR and Ras-Raf-MEK-ERK pathways [35]. Further demonstrating this interconnectedness is usually a report suggesting that AKT upregulates macrophage inhibitory cytokine-1 (MIC-1) expression, Col11a1 which in turn increases activation of ERK1 [36]. Additional pathways that regulate AKTs include mRNA methylation of upstream AKT regulators, aberration of normal miRNA control over AKT and its regulators, changes in ubiquitination of the PH domain name, causing failure to localize to the membrane, and changes in regulation by lncRNAs [26]. Current literature on isoform-specific roles of AKT in cancer progression is usually full of contradictions. Despite lack of total consensus, literature favors the possibility that AKT1 is usually involved in increased proliferation and tumor growth as well as decreased apoptosis, whereas AKT2 is usually associated with increased migration, invasion, and metastasis. AKT3 appears to play a role in increasing both proliferation and metastasis [37]. Inhibition of AKT1 in MMTV-ErbB2/neu and MMTV-PyMT-induced mouse mammary tumors results in diminished tumor development due to lower expression of Ki-67 and cyclin D and increased apoptosis [38]. The protumorigenic role of AKT1 is usually evident from a study on miR-409-3p. miR-409-3p reduced proliferation, decreased invasion and migration of breast cancer cells in vitro by downregulating AKT1 [39]. Few studies have described the tumor suppressor role of AKT1 in breast cancer. For example, reduced activity of AKT1 has been associated with a dysregulation of p53 and DNA-damage induced transcription [40]. In another study, AKT1 was observed to be central to the reduction of breast cancer invasiveness by another tumor suppressor called TIS21. Specifically, TIS21 impacts motility and metastasis by reducing the assembly of the cytoskeleton. This TIS21-mediated decrease in cancer cell motility involves AKT1-dependent downregulation of diaphanous-related formin and decreased NOX4-mediated ROS formation [41]. Additional support for antimetastatic activity of AKT1 came INK 128 (MLN0128) from studies that examined the role of CXCR2 in metastasis. CXCR2-mediated breast cancer metastasis corelated with lower AKT1 expression [42]. Interestingly, we reported distinct prognostic significance of AKT in breast cancer based on subcellular localization. Nuclear localization of activated AKT (pS473) is usually associated with better prognosis [43]. Few of the discrepancies noted in the literature could, therefore, be due to lack of consideration to subcellular distribution of phosphorylated AKT in experimental models. Like AKT1, the role of the AKT2 isoform in breast cancer is usually complex and there are conflicting reports in the literature. Many studies have implicated AKT2 in proliferation and metastasis of various cancers. In a lung cancer cell line, for example, knockdown of AKT2 resulted in lower proliferation and invasiveness, which correlated with reduced retinoblastoma (RB) phosphorylation and COX2 expression [44]. In PTEN-deficient prostate tumors, AKT2 is necessary for growth and survival [45]. In breast cancer, AKT2 may increase metastatic potential via several mechanisms. For example, upregulation of AKT2 causes 1-integrin-mediated increase in INK 128 (MLN0128) adhesion and invasion via collagen IV. In this regard, AKT2 was.