title: Decreased LRIG1 in fulvestrant-treated luminal breast cancer cells permits ErbB3 upregulation and increased growth.
abstract: ErbB3, a member of the ErbB family of receptor tyrosine kinases, is a potent activator of phosphatidyl inositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) signaling, driving tumor cell survival and therapeutic resistance in breast cancers. In luminal breast cancers, ErbB3 upregulation following treatment with the antiestrogen fulvestrant enhances PI3K/mTOR-mediated cell survival. However, the mechanism by which ErbB3 is upregulated in fulvestrant-treated cells is unknown. We found that ErbB3 protein levels and cell surface presentation were increased following fulvestrant treatment, focusing our attention on proteins that regulate ErbB3 at the cell surface, including Nrdp1, NEDD4 and LRIG1. Among these, only LRIG1 correlated positively with ERα, but inversely with ErbB3 in clinical breast cancer data sets. LRIG1, an estrogen-inducible ErbB downregulator, was decreased in a panel of fulvestrant-treated luminal breast cancer cells. Ectopic LRIG1 expression from an estrogen-independent promoter uncoupled LRIG1 from estrogen regulation, thus sustaining LRIG1 and maintaining low ErbB3 levels in fulvestrant-treated cells. An LRIG1 mutant lacking the ErbB3 interaction motif was insufficient to downregulate ErbB3. Importantly, LRIG1 overexpression improved fulvestrant-mediated growth inhibition, whereas cells expressing the LRIG1 mutant were poorly sensitive to fulvestrant, despite effective ERα downregulation. Consistent with these results, LRIG1 expression correlated positively with increased disease-free survival in antiestrogen-treated breast cancer patients. These data suggest that ERα-dependent expression of LRIG1 dampens ErbB3 signaling in luminal breast cancer cells, and by blocking ERα activity with fulvestrant, LRIG1 is decreased thus permitting ErbB3 accumulation, enhanced ErbB3 signaling to cell survival pathways and blunting therapeutic response to fulvestrant.
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Morrison
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Williams
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Vaught
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Hicks
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lim
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: C
authors.initials: C
authors.lastname: McKernan
authors.affiliation: Takis Biotech, via di Castel Romano 100, 00128 Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Aurisicchio
authors.affiliation: Takis Biotech, via di Castel Romano 100, 00128 Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Ciliberto
authors.affiliation: IRCCS National Cancer Institute 'G Pascale', via Mariano Semmola, 83131 Naples, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Simion
authors.affiliation: IRCCS National Cancer Institute 'G Pascale', via Mariano Semmola, 83131 Naples, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Sweeney
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.|The Vanderbilt Ingram Cancer Center, Nashville, TN, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Cook
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D004967:Estrogens / Q000235:genetics; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D020893:Receptor, ErbB-3 / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins; D000077267:Fulvestrant; D004958:Estradiol; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3