Abstract
While endocrine therapy is the mainstay of ER+ breast cancer, the clinical effectiveness of these agents is limited by the phenomenon of acquired resistance that is associated with disease relapse and poor prognosis. Our previous studies revealed that acquired resistance is accompanied by a gain in cellular invasion and migration and also that CD44 family proteins are overexpressed in the resistant phenotype. Given the association of CD44 with tumor progression, we hypothesized that its overexpression may act to promote the aggressive behavior of endocrine-resistant breast cancers. Here, we have investigated further the role of two specific CD44 isoforms, CD44v3 and CD44v6, in the endocrine-resistant phenotype. Our data revealed that overexpression of CD44v6, but not CD44v3, in endocrine-sensitive MCF-7 cells resulted in a gain in EGFR signaling, enhanced their endogenous invasive capacity, and attenuated their response to endocrine treatment. Suppression of CD44v6 in endocrine-resistant cell models was associated with a reduction in their invasive capacity. Our data suggest that upregulation of CD44v6 in acquired resistant breast cancer may contribute to a gain in the aggressive phenotype of these cells and loss of endocrine response through transactivation of the EGFR pathway. Future therapeutic targeting of CD44v6 may prove to be an effective strategy alongside EGFR-targeted agents in delaying/preventing acquired resistance in breast cancer.
Highlights
Over two-thirds of breast cancers express the estrogen receptor and are, likely to respond to endocrine therapies exemplified by tamoxifen [1, 2]
These data pointed to an upregulation of both CD44 and receptor for HA-mediated motility (HMMR/RHAMM) in Tam-R and Fas-R models compared to MCF-7 cells, while expression of other hyaladherin members, lymphatic vessel endothelial receptor 1 (LYVE-1), toll-like receptor 4 (TL4), stabilin 2 (STAB-2), ICAM1, and VCAN were suppressed
Current endocrine treatments for ER+ breast cancers work well, the phenomenon of acquired resistance still represents a major limiting factor in their overall effectiveness and resistant disease frequently occurs at distant sites with associated poor prognosis
Summary
Over two-thirds of breast cancers express the estrogen receptor and are, likely to respond to endocrine therapies exemplified by tamoxifen [1, 2]. A greater understanding of the molecular pathways associated with resistance is needed in order to highlight better therapeutic opportunities. To this end, we have previously reported that acquired tamoxifen resistance in CD44v6 and Endocrine Resistance breast cancer is accompanied by the overexpression of the CD44 transmembrane receptor protein that appears to contribute to their aggressive phenotype through modulation of growth factor receptor signaling. CD44v6 is implicated in the tumorigenesis and migration of tumor cells during metastasis [14, 15] while overexpression of CD44v6 is suggested to predict overall survival (OS) and disease-free survival (DFS) in breast and other cancers [16,17,18]. In many of these cases, it is the co-expression of CD44 isoforms alongside other growth factor receptors that confers a poor prognostic signature
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