Acquired resistance to selective estrogen receptor modulators (SERMs) in clinical practice (tamoxifen & raloxifene) by selection pressure in breast cancer cell populations

Abstract

Tamoxifen, a pioneering selective estrogen receptor modulator (SERM), has long been a therapeutic choice for all stages of estrogen receptor (ER)-positive breast cancer. The clinical application of long-term adjuvant antihormone therapy for the breast cancer has significantly improved breast cancer survival. However, acquired resistance to SERM remains a significant challenge in breast cancer treatment. The evolution of acquired resistance to SERMs treatment was primarily discovered using MCF-7 tumors transplanted in athymic mice to mimic years of adjuvant treatment in patients. Acquired resistance to tamoxifen is unique because the growth of resistant tumors is dependent on SERMs. It appears that acquired resistance to SERM is initially able to utilize either E2 or a SERM as the growth stimulus in the SERM-resistant breast tumors. Mechanistic studies reveal that SERMs continuously suppress nuclear ER-target genes even during resistance, whereas they function as agonists to activate multiple membrane-associated molecules to promote cell growth. Laboratory observations in vivo further show that three phases of acquired SERM-resistance exists, depending on the length of SERMs exposure. Tumors with Phase I resistance are stimulated by both SERMs and estrogen. Tumors with Phase II resistance are stimulated by SERMs, but are inhibited by estrogen due to apoptosis. The laboratory models suggest a new treatment strategy, in which limited-duration, low-dose estrogen can be used to purge Phase II-resistant breast cancer cells. This discovery provides an invaluable insight into the evolution of drug resistance to SERMs, and this knowledge is now being used to justify clinical trials of estrogen therapy following long-term antihormone therapy. All of these results suggest that cell populations that have acquired resistance are in constant evolution depending upon selection pressure. The limited availability of growth stimuli in any new environment enhances population plasticity in the trial and error search for survival.

Effect of single mutagenesis on the binding pocket of canine estrogen receptor alpha: Structure and binding affinity

“…It should be kept in mind that different algorithms could give rise to different structural prediction and possibly different binding affinities [21,[24][25][26] . The acquired SERM resistance in breast cancer cells has been studied, especially with respect to long-term treatment [27][28][29][30][31][32] . Interestingly, ER expression is maintained in the acquired resistant tumors [29] .…”

The function of membrane-associated molecules in acquired resistance to antiestrogens in breast cancer

“…Long-term therapy generates selection pressure for cell populations that evolve from acquired SERM resistance, ubiquitously observed in metastatic breast cancer, to eventually expose a vulnerability that is expressed as E2-induced apoptosis [3][4][5] . Laboratory observations further show that three phases of acquired SERM-resistance exist (Figure 1), which depend on the length of SERMs exposure [4,6,7] . Tumors with phase I resistance are stimulated by E2 and SERMs, but inhibited by aromatase inhibitors (AIs) and…”

“…fulvestrant; tumors with phase II resistance are stimulated by SERMs, but are inhibited by E2 due to apoptosis; tumors with phase III resistance grow autonomously regardless of SERMs, but are inhibited by E2 with apoptosis [4,6,7] . The cell populations are clearly being modulated over years of therapy so that those cells that can adapt and grow in new environment [4,6,7] .…”

“…The cell populations are clearly being modulated over years of therapy so that those cells that can adapt and grow in new environment [4,6,7] . Understanding this process provides an opportunity to save more lives.…”

“…RHOF, belonging to the Rho family GTPases, has a critical role in controlling the formation of filopodia [22] . It is unclear the biological [4,7] . Reprint with permission [7].…”