Sensitivity to the Aromatase Inhibitor Letrozole Is Prolonged After a “Break” in Treatment

Abstract

Using a hormone-dependent xenograft model, we established that loss of response to letrozole was accompanied by upregulation of the Her-2/mitogen-activated protein kinase (MAPK) pathway and downregulation of estrogen receptor α (ERα) and aromatase activity. In our previous study, we showed that stopping letrozole treatment or adding trastuzumab could reverse acquired resistance. In this study, we compared the effects of intermittent letrozole treatment and switching treatment between letrozole and trastuzumab on tumor growth in an attempt to optimize discontinuous letrozole treatment. The mice were treated with letrozole until the tumors developed resistance and then were divided into three groups: (a) letrozole, (b) trastuzumab, and (c) "off" (Δ 4 A supplement only); tumors were collected every week to examine changes in tumor protein expression and activity. In off group tumors, Her-2/p-MAPK activation gradually decreased and ERα and aromatase protein (and activity) increased. Within the first week of trastuzumab treatment, Her-2 and MAPK were downregulated and ERα was upregulated. When letrozole-resistant MCF-7Ca tumors were taken off treatment for 4 weeks, the second course of letrozole treatment provided a much longer duration of response (P = 0.02). However, switching treatment to trastuzumab for 4 weeks did not provide any inhibition of tumor growth. Our studies revealed that the adaptation of cells to a low-estrogen environment by upregulation of Her-2/MAPK and downregulation of ERα/aromatase was reversed on letrozole withdrawal. The tumors once again became responsive to letrozole for a significant period. These results suggest that response to letrozole can be prolonged by a short "break" in the treatment. Mol Cancer Ther; 9(1); 46-56.

Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers

“…This has also been confirmed in xenograft models where adaption of the cells to low estrogen levels is accompanied by up-regulation of HER-2/neu and downregulation of ER and aromatase activity [12,13]. Thus, increased expression or activation of growth factor receptors and cross-talk between ER-and alternate growth factor signaling pathways may cause endocrine resistance [14][15][16][17][18][19][20].…”

A nude mouse model of obesity to study the mechanisms of resistance to aromatase inhibitors

“…Letrozole and D 4 A for injection were prepared using 0.3% weight per volume (w/v) hydroxypropyl cellulose (HPC) in 0.9% w/v NaCl solution and injected s.c. five times weekly. The doses of letrozole (10 mg/day) and D 4 A (100 mg/day) used are as previously determined and reported (Sabnis et al 2008(Sabnis et al , 2010.…”

Combination of trastuzumab and letrozole after resistance to sequential trastuzumab and aromatase inhibitor monotherapies in patients with estrogen receptor-positive, HER-2-positive advanced breast cancer: a proof-of-concept trial (SAKK 23/03)

“…Several reports suggest that a bidirectional cross talk between ER, HER-2, and other members of the EGFR family play a key role in the resistant model systems (Osborne et al 2005, Sabnis et al 2005, Arpino et al 2008 and that inhibition of only one pathway leads to the activation of the other. Loss of response to letrozole was accompanied by up-regulation of the HER-2/mitogen-activated protein kinase pathway and down-regulation of ER and aromatase activity (Sabnis et al 2010). In addition, preclinical models with trastuzumab (Sabnis et al 2009), gefitinib (Massarweh et al 2006), or lapatinib (Xia et al 2006) have consistently shown that inhibition of the growth factor activity in endocrineresistant cells could be associated with an adoptive increase in ER signaling and subsequent restoration of sensitivity to endocrine treatment.…”