title: Androgen receptor signaling pathways as a target for breast cancer treatment.
abstract: The androgen receptor (AR) is a ligand-dependent transcription factor, and its effects on breast range from physiological pubertal development and age-related modifications to cancer onset and proliferation. The prevalence of AR in early breast cancer is around 60%, and AR is more frequently expressed in ER-positive than in ER-negative tumors. We offer an overview of AR signaling pathways in different breast cancer subtypes, providing evidence that its oncogenic role is likely to be different in distinct biological and clinical scenarios. In particular, in ER-positive breast cancer, AR signaling often antagonizes the growth stimulatory effect of ER signaling; in triple-negative breast cancer (TNBC), AR seems to drive tumor progression (at least in luminal AR subtype of TNBC with a gene expression profile mimicking luminal subtypes despite being negative to ER and enriched in AR expression); in HER2-positive breast cancer, in the absence of ER expression, AR signaling has a proliferative role. These data represent the rationale for AR-targeting treatment as a potentially new target therapy in breast cancer subset using androgen agonists in some AR-positive/ER-positive tumors, AR antagonists in triple-negative/AR-positive tumors and in combination with anti-HER2 agents or with other signaling pathways inhibitors (including PI3K/MYC/ERK) in HER2-positive/AR-positive tumors. Only the ongoing and future prospective clinical trials will allow us to establish which agents are the best option in every specific condition, keeping in mind that there is evidence of opposite androgens and AR agonist/antagonist drug effects on cell proliferation particularly in AR-positive/ER-positive tumors.
authors.affiliation: Department of Medical OncologyIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì-Cesena, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pietri
authors.affiliation: Department of Medical OncologyIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì-Cesena, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Conteduca
authors.affiliation: Unit of Biostatistics and Clinical TrialsIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì-Cesena, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Andreis
authors.affiliation: Unit of Biostatistics and Clinical TrialsIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì-Cesena, Italy ilaria.massa@irst.emr.it andrea.rocca@irst.emr.it.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Massa
authors.affiliation: Department of Medical OncologyIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì-Cesena, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Melegari
authors.affiliation: Department of Medical OncologyIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì-Cesena, Italy.
authors.forename: Samanta
authors.initials: S
authors.lastname: Sarti
authors.affiliation: Department of Medical OncologyIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì-Cesena, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cecconetto
authors.affiliation: Department of Medical OncologyIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì-Cesena, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Schirone
authors.affiliation: Biosciences LaboratoryIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì-Cesena, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Bravaccini
authors.affiliation: Unit of Biostatistics and Clinical TrialsIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì-Cesena, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Serra
authors.affiliation: Department of Medical OncologyIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì-Cesena, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Fedeli
authors.affiliation: Department of Medical OncologyIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì-Cesena, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Maltoni
authors.affiliation: Department of Medical OncologyIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì-Cesena, Italy.
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.affiliation: Department of Medical OncologyIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì-Cesena, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: De Giorgi
authors.affiliation: Department of Medical OncologyIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì-Cesena, Italy ilaria.massa@irst.emr.it andrea.rocca@irst.emr.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rocca
mesh_terms: D059002:Androgen Receptor Antagonists / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000235:genetics* / Q000628:therapy*; D005260:Female; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D011944:Receptors, Androgen
keywords: AR-targeting therapy; androgen receptor; androgen receptor structure; breast cancer; signaling pathway