Abstract
Despite the effectiveness of endocrine therapies in estrogen receptor positive (ER+) breast cancer, approximately 40% of patients relapse. Previously, we identified the Focal-adhesion kinase canonical pathway as a major contributor of resistance to estrogen deprivation and cellular-sarcoma kinase (c-src) as a dominant gene in this pathway. Dasatinib, a pan-src inhibitor, has recently been used in clinical trials to treat ER+ patients but has shown mixed success. In the following study, using isogenic cell line models, we provide a potential explanation for these findings and suggest a sub-group that may benefit. A panel of isogenic cell lines modelling resistance to aromatase inhibitors (LTED) and tamoxifen (TAMR) were assessed for response to dasatinib ± endocrine therapy. Dasatinib caused a dose-dependent decrease in proliferation in MCF7-TAMR cells and resensitized them to tamoxifen and fulvestrant but not in HCC1428-TAMR. In contrast, in estrogen-deprived conditions, dasatinib increased the proliferation rate of parental-MCF7 cells and had no effect on MCF7-LTED or HCC1428-LTED. Treatment with dasatinib caused a decrease in src-phosphorylation and inhibition of downstream pathways, including AKT and ERK1/2 in all cell lines tested, but only the MCF7-TAMR showed a concomitant decrease in markers of cell cycle progression. Inhibition of src also caused a significant decrease in cell migration in both MCF7-LTED and MCF7-TAMR cells. Finally, we showed that, in MCF7-TAMR cells, in contrast to tamoxifen sensitive cell lines, ER is expressed throughout the cell rather than being restricted to the nucleus and that treatment with dasatinib resulted in nuclear shuttling of ER, which was associated with an increase in ER-mediated transcription. These data suggest that src has differential effects in endocrine-resistant cell lines, particularly in tamoxifen resistant models, with low ER genomic activity, providing further evidence of the importance of patient selection for clinical trials testing dasatinib utility in ER+ breast cancer.
Highlights
Over 80% of breast cancers (BC) are estrogen receptor (ER) positive (+) at primary diagnosis
The reliance of ER+ tumours on E has been exploited clinically by the development and use of various endocrine therapies, such as: aromatase inhibitors (AI), which block the conversion of androgens to estrogens; selective ER modulators (SERM), such as tamoxifen, which compete with E for the ER; and fulvestrant (ICI182780), which once bound, potentiates degradation of ER [2]
Using global gene expression data derived from cells adapted to long-term-E-deprivation (LTED), we showed that the Focal adhesion kinase (FAK) pathway, was one of the major pathways upregulated at the point of resistance and revealed cellular sarcoma kinase (c-src), as the major gene elevated in this pathway [3]
Summary
Over 80% of breast cancers (BC) are estrogen receptor (ER) positive (+) at primary diagnosis. Estrogen (E) mediates its effects by binding to the ER. E-bound ER associates classically with E-response-elements (EREs) on target genes controlling proliferation and cell survival. ER has been shown in-vitro to function via non-genomic mechanisms by association with growth factor signalling pathways [1]. The reliance of ER+ tumours on E has been exploited clinically by the development and use of various endocrine therapies, such as: aromatase inhibitors (AI), which block the conversion of androgens to estrogens; selective ER modulators (SERM), such as tamoxifen, which compete with E for the ER; and fulvestrant (ICI182780), which once bound, potentiates degradation of ER [2]. Despite the effectiveness of these current therapies, BC cells can circumvent the need for steroid hormones and resistance commonly occurs in approximately 40% of women, prioritizing the need to identify therapies to overcome this
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