title: Overexpression of Specific CD44 Isoforms Is Associated with Aggressive Cell Features in Acquired Endocrine Resistance.
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.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University , Cardiff , UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bellerby
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University , Cardiff , UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Smith
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University , Cardiff , UK.
authors.forename: Sue
authors.initials: S
authors.lastname: Kyme
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University , Cardiff , UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Gee
authors.affiliation: Institute of Pathology, University Hospital of Basel , Basel , Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Günthert
authors.affiliation: Faculty of Medicine and Health Sciences, University of Nottingham , Nottingham , UK.
authors.forename: Andy
authors.initials: A
authors.lastname: Green
authors.affiliation: Faculty of Medicine and Health Sciences, University of Nottingham , Nottingham , UK.
authors.forename: Emad
authors.initials: E
authors.lastname: Rakha
authors.affiliation: Velindre Cancer Centre , Cardiff , UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Barrett-Lee
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University , Cardiff , UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hiscox
keywords: CD44; breast cancer; endocrine resistance; invasion