title: Development of resistance to targeted therapies transforms the clinically associated molecular profile subtype of breast tumor xenografts.
abstract: The effectiveness of therapies targeting specific pathways in breast cancer, such as the estrogen receptor or HER2, is limited because many tumors manifest resistance, either de novo or acquired, during the course of treatment. To investigate molecular mechanisms of resistance, we used two xenograft models of estrogen receptor-positive (ER+) breast cancer, one with and one without HER2 overexpression (MCF7/HER2-18 and MCF7 wt, respectively). Mice with established tumors were assigned to the following treatment groups: estrogen supplementation (E2), estrogen deprivation (ED), ED plus tamoxifen (Tam), all with or without the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (G). Another group received ED plus the antiestrogen fulvestrant (MCF7 wt only). Tumors with acquired or de novo resistance to these endocrine therapies were profiled for gene expression and compared with tumors in the E2 control group. One class of genes underexpressed in endocrine-resistant tumors (relative to E2-treated tumors) were estrogen inducible in vitro and associated with ER+ human breast cancers (luminal subtype). Another class of genes overexpressed in tumors with acquired resistance in both models represented transcriptional targets of HER2 signaling and was associated with ER-/HER2+ human cancers (ERBB2+ subtype). A third class of genes overexpressed in MCF7/HER2-18 tumors exhibiting de novo resistance to tamoxifen was associated with ER+ human cancers but not with estrogen-regulated genes. Thus, in response to various endocrine therapy regimens, these xenograft breast tumors shut down classic estrogen signaling and activate alternative pathways such as HER2 that contribute to treatment resistance. Over time, the molecular phenotype of breast cancer can change.
authors.affiliation: The Dan L. Duncan Cancer Center, Baylor College of Medicine, Room N1230.02, One Baylor Plaza-BCM 600, Houston, TX 77030, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Suleiman
authors.initials: S
authors.lastname: Massarweh
authors.forename: Shixia
authors.initials: S
authors.lastname: Huang
authors.forename: Anna
authors.initials: A
authors.lastname: Tsimelzon
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.forename: Jiang
authors.initials: J
authors.lastname: Shou
authors.forename: Luca
authors.initials: L
authors.lastname: Malorni
authors.forename: Rachel
authors.initials: R
authors.lastname: Schiff
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000378:metabolism; D004967:Estrogens / Q000172:deficiency; D000077267:Fulvestrant; D000077156:Gefitinib; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010052:Ovariectomy; D011799:Quinazolines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004958:Estradiol; D047628:Estrogen Receptor alpha; D004967:Estrogens; D000077267:Fulvestrant; D000077156:Gefitinib; D011799:Quinazolines; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen
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