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 alpha (
ERalpha) 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" (Delta(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
ERalpha and
aromatase protein (and activity) increased. Within the first week of
trastuzumab treatment, Her-2 and MAPK were downregulated and
ERalpha 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
ERalpha/
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.