Retinoids and breast cancer: from basic studies to the clinic and back again.
All-trans retinoic acid (ATRA) is the most important active metabolite of vitamin A controlling segmentation in the developing organism and the homeostasis of various tissues in the adult. ATRA as well as natural and synthetic derivatives, collectively known as retinoids, are also promising agents in the treatment and chemoprevention of different types of neoplasia including breast cancer. The major aim of the present article is to review the basic knowledge acquired on the anti-tumor activity of classic retinoids, like ATRA, in mammary tumors, focusing on the underlying cellular and molecular mechanisms and the determinants of retinoid sensitivity/resistance. In the first part, an analysis of the large number of pre-clinical studies available is provided, stressing the point that this has resulted in a limited number of clinical trials. This is followed by an overview of the knowledge acquired on the role played by the retinoid nuclear receptors in the anti-tumor responses triggered by retinoids. The body of the article emphasizes the potential of ATRA and derivatives in modulating and in being influenced by some of the most relevant cellular pathways involved in the growth and progression of breast cancer. We review the studies centering on the cross-talk between retinoids and some of the growth-factor pathways which control the homeostasis of the mammary tumor cell. In addition, we consider the cross-talk with relevant intra-cellular second messenger pathways. The information provided lays the foundation for the development of rational and retinoid-based therapeutic strategies to be used for the management of breast cancer.
Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy. Electronic address: enrico.garattini@marionegri.it.
Enrico
E
Garattini
Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy. Electronic address: marco.bolis@marionegri.it.
Marco
M
Bolis
Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy. Electronic address: silvioken@hotmail.it.
Silvio Ken
SK
Garattini
Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy. Electronic address: maddalena.fratelli@marionegri.it.
Maddalena
M
Fratelli
Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy. Electronic address: floriana.centritto@marionegri.it.
Floriana
F
Centritto
Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy. Electronic address: gabriela.paroni@marionegri.it.
Gabriela
G
Paroni
Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy. Electronic address: maurizio.gianni@marionegri.it.
Maurizio
M
Gianni'
Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy. Electronic address: adriana.zanetti@marionegri.it.
Adriana
A
Zanetti
Laboratory of Experimental Oncology and Pharmacogenomics, IRCCS-Fondazione S. Maugeri, Università degli Studi di Pavia, via Maugeri 10, 27100 Pavia, Italy. Electronic address: anna.pagani@fsm.it.
Anna
A
Pagani
Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy. Electronic address: jamesneil.fisher@marionegri.it.
James Neil
JN
Fisher
Laboratory of Experimental Oncology and Pharmacogenomics, IRCCS-Fondazione S. Maugeri, Università degli Studi di Pavia, via Maugeri 10, 27100 Pavia, Italy. Electronic address: alberto.zambelli@fsm.it.
Alberto
A
Zambelli
Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy. Electronic address: mineko.terao@marionegri.it.
Mineko
M
Terao
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002986:Clinical Trials as Topic; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D039781:PubMed; D020239:Receptor Cross-Talk / Q000187:drug effects; D051880:Receptors, Notch / Q000378:metabolism; D012176:Retinoids / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*; D051153:Wnt Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D051880:Receptors, Notch; D012176:Retinoids; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D014212:Tretinoin; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
Breast cancer; Chemo-prevention; Gene pathways; RAR/RXR; Retinoic acid; Treatment