title: Lrig1 is an estrogen-regulated growth suppressor and correlates with longer relapse-free survival in ERα-positive breast cancer.
abstract: Lrig1 is the founding member of the Lrig family and has been implicated in the negative regulation of several oncogenic receptor tyrosine kinases including ErbB2. Lrig1 is expressed at low levels in several cancer types but is overexpressed in some prostate and colorectal tumors. Given this heterogeneity, whether Lrig1 functions to suppress or promote tumor growth remains a critical question. Previously, we found that Lrig1 was poorly expressed in ErbB2-positive breast cancer, suggesting that Lrig1 has a growth-inhibitory role in this tumor type. However, breast cancer is a complex disease, with ErbB2-positive tumors accounting for just 25% of all breast cancers. To gain a better understanding of the role of Lrig1 in breast cancer, we examined its expression in estrogen receptor α (ERα)-positive disease which accounts for the majority of breast cancers. We find that Lrig1 is expressed at significantly higher levels in ERα-positive disease than in ERα-negative disease. Our study provides a molecular rationale for Lrig1 enrichment in ERα-positive disease by showing that Lrig1 is a target of ERα. Estrogen stimulates Lrig1 accumulation and disruption of this induction enhances estrogen-dependent tumor cell growth, suggesting that Lrig1 functions as an estrogen-regulated growth suppressor. In addition, we find that Lrig1 expression correlates with prolonged relapse-free survival in ERα-positive breast cancer, identifying Lrig1 as a new prognostic marker in this setting. Finally, we show that ErbB2 activation antagonizes ERα-driven Lrig1 expression, providing a mechanistic explanation for Lrig1 loss in ErbB2-positive breast cancer. This work provides strong evidence for a growth-inhibitory role for Lrig1 in breast cancer.
authors.affiliation: Division of Basic Sciences, University of California Davis Cancer Center, Sacramento, CA 95817, USA.
authors.forename: Sheryl R
authors.initials: SR
authors.lastname: Krig
authors.forename: Seth
authors.initials: S
authors.lastname: Frietze
authors.forename: Catalina
authors.initials: C
authors.lastname: Simion
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Miller
authors.forename: Will H D
authors.initials: WH
authors.lastname: Fry
authors.forename: Hanine
authors.initials: H
authors.lastname: Rafidi
authors.forename: Lakmal
authors.initials: L
authors.lastname: Kotelawala
authors.forename: Lihong
authors.initials: L
authors.lastname: Qi
authors.forename: Obi L
authors.initials: OL
authors.lastname: Griffith
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.forename: Kermit L
authors.initials: KL
authors.lastname: Carraway
authors.forename: Colleen
authors.initials: C
authors.lastname: Sweeney
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins