Resistance to endocrine therapy in breast cancer: molecular mechanisms and future goals.

INTRODUCTION: The majority of breast cancers (BCs) are characterized by the expression of estrogen receptor alpha (ERα+). ERα acts as ligand-dependent transcription factor for genes associated with cell survival, proliferation, and tumor growth. Thus, blocking the estrogen agonist effect on ERα is the main strategy in the treatment of ERα+ BCs. However, despite the development of targeted anti-estrogen therapies for ER+ BC, around 30-50% of early breast cancer patients will relapse. Acquired resistance to endocrine therapy is a great challenge in ER+ BC patient treatment. DISCUSSION: Anti-estrogen resistance is a consequence of molecular changes, which allow for tumor growth irrespective of estrogen presence. Those changes may be associated with ERα modifications either at the genetic, regulatory or protein level. Additionally, the activation of alternate growth pathways and/or cell survival mechanisms can lead to estrogen-independence and endocrine resistance. CONCLUSION: This comprehensive review summarizes molecular mechanisms associated with resistance to anti-estrogen therapy, focusing on genetic alterations, stress responses, cell survival mechanisms, and cell reprogramming.

SOX11 expression as a MRD molecular marker for MCL in comparison with t(11;14) and IGH rearrangement.

The main cause of death in mantle cell lymphoma (MCL) patients is relapse due to undetermined minimal residual disease (MRD) and therefore monitoring MRD is crucial for making the best treatment decisions. The gold standard method for MRD analysis is the quantitative polymerase chain reaction. The most commonly used molecular markers for measuring MRD in MCL are: t(11;14)(q13;p32) translocation or CCND1 expression and IGH rearrangement. Such markers can, however, be found in other B cell non-Hodgkin lymphomas. Recent studies demonstrate that SOX11 expression is highly specific for MCL and could be used as a marker for measuring MRD. Moreover, evidence shows that SOX11 level could be predictive for overall survival (OS) and progression-free survival (PFS). We have measured MRD level in follow-up samples from 27 patients diagnosed with MCL using the molecular markers: t(11;14), IGH rearrangement and SOX11 expression. We compared all markers by their sensitivity, utility and quantitative range. We also examined the predictive value of SOX11 expression for OS and PFS. SOX11 expression was found to have better specificity, quantitative range and utility than the t(11;14). The predictive value of SOX11 expression was confirmed. At diagnosis, patients with high SOX11 expression had shorter PFS than patients with low SOX11 expression (p = 0.04*); differences between OS being statistically insignificant. To our best knowledge this is a first study comparing SOX11 with t(11;14) and IGH rearrangement as markers of MRD level. Moreover, in this study we confirmed that SOX11 is useful in cases when other molecular markers cannot be used.