title: Novel mechanisms of resistance to endocrine therapy: genomic and nongenomic considerations.
abstract: Selective estrogen receptor (ER) modulators have been the most commonly used neoadjuvant therapy for hormone-dependent breast cancer. However, resistance to endocrine therapy, either inherent or acquired during treatment, presents a major challenge in disease management. The causes of resistance to hormone therapy are not well understood and are the subject of active investigation. It is increasingly clear that decreasing sensitivity of ER-positive breast cancer cells to antiestrogens is caused by several factors. Cross talk between ER and growth factor signaling has emerged as a critical factor in endocrine resistance. Here, we present evidence that receptor tyrosine kinase signaling also plays a role in resistance by controlling the subcellular localization of ER signaling components. Localization of ER in either the nuclear or cytoplasmic compartments has functional implications. Recent work suggests that dynein light chain 1, a recently identified substrate of p21-activated kinase 1, modulates ER transactivation functions through a novel ER coactivator function. Likewise, receptor tyrosine kinase signaling can also alter the expression of ER coregulators such as metastasis-associated antigen 1, leading to hormonal independence. Furthermore, proline-, glutamic acid-, leucine-rich protein 1, an ER coactivator involved in both genomic and nongenomic signaling pathways, is activated by epidermal growth factor receptor and plays a prominent role in resistance to tamoxifen. These recent advances suggest new targeted therapeutic approaches that may lead to either reversion or prevention of endocrine resistance in breast tumors.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Anupama E
authors.initials: AE
authors.lastname: Gururaj
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Rayala
authors.forename: Ratna K
authors.initials: RK
authors.lastname: Vadlamudi
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D020239:Receptor Cross-Talk / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D020794:Receptor Protein-Tyrosine Kinases