Endocrine Resistance in Breast Cancer: Focus on the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Signaling Pathway

Abstract

Breast cancer is the most common cancer among women. Up to 75% of breast cancers express the estrogen receptor (ER)α and/or the progesterone receptor (PR). Patients with hormone receptor-positive metastatic breast cancer are typically treated with endocrine therapy. Yet, not all patients with metastatic breast cancer respond to endocrine treatments and are considered to have primary (de novo) resistance. Furthermore, all patients who initially respond to endocrine treatment will eventually develop acquired resistance. Several mechanisms have been linked to the development of endocrine resistance, including reduced expression of ERα, altered regulation of the ER pathway, and activation of various growth factor signaling pathways, among them the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. This pathway is involved in critical processes including cell survival, proliferation, and angiogenesis, and plays a central role in breast cancer development. Recent laboratory and clinical data implicate this pathway as mediating endocrine resistance, and agents directed against critical components of this pathway are either already approved for clinical use in breast cancer patients or are currently being tested in clinical trials. In this review, we describe the interaction between the PI3K/Akt/mTOR pathway and the ER cascade, its role in mediating endocrine resistance, and the clinical implications of this interaction.

The PI3K Pathway: Background and Treatment Approaches

“…1) [9]. The respective receptor dimerizes, is autophosphorylated and recruits adaptor proteins such as insulin receptor substrate (IRS)1 and IRS2.…”

“…Activation of mTORC1 also leads to a negative feedback loop [9]. Direct inhibition of mTORC1 by an administered treatment can suspend the negative feedback loop, leading to the paradoxical activation of the signaling pathway and expression of multiple receptor tyrosine kinases such as HER2 and the IGF-1 receptor (IGF-1R) [11].…”

“…Subsequently, an association was demonstrated between the activation of Akt or reduced PTEN expression and endocrine resistance in patients with metastatic breast carcinoma or recurrences after tamoxifen therapy [13,14]. Inhibition of Akt via the PI3K signaling pathway may in turn restore sensitivity to tamoxifen, aromatase inhibitors, and also fulvestrant [9]. …”

Roles for miRNAs in endocrine resistance in breast cancer

“…Apoptotic and cell survival signals are also dysregulated in TAM-resistant cells (Riggins et al 2005). A more extensive review of mechanisms promoting endocrine resistance can be found in (Hasson, et al 2013; Musgrove and Sutherland 2009; Zhao and Ramaswamy 2014). Additional factors are continually identified as playing roles in endocrine resistance.…”

Pathway-Oriented Concepts in Adjuvant and Neoadjuvant Breast Cancer Therapy

“…As reported in the third review article of this journal's edition by Hasson and colleagues [6], even if the mechanism of crosstalk between the mTOR and HR pathways are not well described, clinical data support the use of mTOR inhibitors in patients who developed resistance to endocrine treatment. In metastatic breast cancer, the addition of an mTOR inhibitor has shown a gain in survival when combined either with an aromatase inhibitor or with tamoxifen.…”