title: Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones.
abstract: Development of resistance to endocrine therapy is a clinical issue in estrogen receptor (ER)-positive breast cancer. Here we show that persistent activation of AKT/mTOR signaling is crucial to the acquisition of letrozole resistance in cell clones generated from MCF-7/AROM-1 aromatase-expressing breast cancer cells after prolonged letrozole exposure. ERα plays a marginal role in this context. As a proof of concept, the association between PI3K/AKT/mTOR signaling and insensitivity to endocrine therapies was confirmed in breast cancer patients who developed early letrozole resistance in neoadjuvant setting. In addition our results suggest that, regardless of the mechanism mediating the activation of AKT/mTOR pathway, either RAD001 or NVP-BEZ235 treatment may represent a promising strategy to overcome acquired resistance to letrozole in breast cancers dependent on AKT/mTOR signaling.
authors.affiliation: Department of Experimental Medicine, Unit of Experimental Oncology, University of Parma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavazzoni
authors.affiliation: Department of Experimental Medicine, Unit of Experimental Oncology, University of Parma, Italy.
authors.forename: Mara A
authors.initials: MA
authors.lastname: Bonelli
authors.affiliation: Department of Experimental Medicine, Unit of Experimental Oncology, University of Parma, Italy. Electronic address: claudia.fumarola@unipr.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fumarola
authors.affiliation: Department of Experimental Medicine, Unit of Experimental Oncology, University of Parma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: La Monica
authors.affiliation: Department of Experimental Medicine, Unit of Experimental Oncology, University of Parma, Italy.
authors.forename: Kinda
authors.initials: K
authors.lastname: Airoud
authors.affiliation: Department of Experimental Medicine, Unit of Experimental Oncology, University of Parma, Italy.
authors.forename: Ramona
authors.initials: R
authors.lastname: Bertoni
authors.affiliation: Department of Experimental Medicine, Unit of Experimental Oncology, University of Parma, Italy.
authors.forename: Roberta R
authors.initials: RR
authors.lastname: Alfieri
authors.affiliation: Department of Experimental Medicine, Unit of Experimental Oncology, University of Parma, Italy; Italian Workers' Compensation Authority (INAIL) Research Center at the University of Parma, Italy.
authors.forename: Maricla
authors.initials: M
authors.lastname: Galetti
authors.affiliation: Department of Experimental Medicine, Unit of Experimental Oncology, University of Parma, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Tramonti
authors.affiliation: Department of Experimental Medicine, Unit of Experimental Oncology, University of Parma, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Galvani
authors.affiliation: Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: Breakthrough Breast Cancer Centre, Institute of Cancer Research, London, UK.
authors.forename: Lesley-Ann
authors.initials: LA
authors.lastname: Martin
authors.affiliation: Breast Cancer Unit, Istituti Ospitalieri di Cremona, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Andreis
authors.affiliation: Breast Cancer Unit, Istituti Ospitalieri di Cremona, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bottini
authors.affiliation: Breast Cancer Unit, Istituti Ospitalieri di Cremona, Italy; Centro di Medicina Molecolare, Istituti Ospitalieri di Cremona, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Generali
authors.affiliation: Department of Experimental Medicine, Unit of Experimental Oncology, University of Parma, Italy.
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Petronini
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D000068338:Everolimus; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D000077289:Letrozole; D020360:Neoadjuvant Therapy; D009570:Nitriles / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; D007093:Imidazoles; D007166:Immunosuppressive Agents; D000077289:Letrozole; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014230:Triazoles; C531198:dactolisib