title: Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer.
abstract: Tamoxifen has been the mainstay of hormonal therapy in both early and advanced breast cancer patients for approximately three decades. The availability of novel compounds such as aromatase inhibitors (AIs) and fulvestrant, with different mechanism of action, is changing the scenario of endocrine treatment of postmenopausal breast cancer patients. In this review article, we have summarized the current knowledge of the mechanisms of resistance to endocrine therapy, in order to derive information that might be useful for therapeutic intervention. We propose that resistance to endocrine therapy is a progressive, step-wise phenomenon induced by the selective pressure of hormonal agents, which leads breast cancer cells from an estrogen-dependent, responsive to endocrine manipulation phenotype to a non-responsive phenotype, and eventually to an estrogen-independent phenotype. In particular, evidence suggests for each 'action' introduced to block estrogen stimulation of breast cancer cells (i.e. treatment with anti-estrogen), there are one or more corresponding 'reactions' that tumor cells can use to escape our attempts to block their growth: estrogen hypersensitivity associated with increased transcriptional activity of estrogen receptor alpha (ERalpha) and/or increased non-genomic activity of ERalpha, estrogen supersensitivity, increased growth factor signaling, suppression of ERalpha expression and finally estrogen independence. Activation of growth factor signaling is involved in each step of this phenomenon, and might ultimately substitute estrogen in sustaining the growth and the survival of breast cancer cells. In this respect, results of pre-clinical and clinical studies with AIs, fulvestrant and signaling inhibitors sustain this hypothesis. More importantly, the knowledge of the mechanisms involved in the resistance of breast cancer cells to endocrine therapy offers potential for novel therapeutic strategies.
authors.affiliation: Cell Biology and Preclinical Models, INT-Fondazione Pascale, Naples, Italy. nicnorm@yahoo.com
authors.forename: Nicola
authors.initials: N
authors.lastname: Normanno
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Maio
authors.forename: Ermelinda
authors.initials: E
authors.lastname: De Maio
authors.forename: Antonella
authors.initials: A
authors.lastname: De Luca
authors.forename: Andrea
authors.initials: A
authors.lastname: de Matteis
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.forename: Francesco
authors.initials: F
authors.lastname: Perrone
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone