title: Letrozole-induced functional changes in carcinoma-associated fibroblasts and their influence on breast cancer cell biology.
abstract: Accumulating evidence suggests that carcinoma-associated fibroblasts (CAFs) influence the efficacy of endocrine therapy. Aromatase inhibitors inhibit the growth of breast tumors by inhibiting the synthesis of estrogen. However, it remains unknown whether the aromatase inhibitor letrozole has an additional impact on CAFs, which further influence the efficacy of endocrine therapy. Primary CAFs were isolated from primary estrogen receptor-positive human breast tumors. Estrogen-deprived culture medium was used to exclude the influence of steroids. In co-culture, primary cultured CAFs increased MCF7 cell adhesion, invasion, migration and proliferation, and letrozole treatment inhibited these increases, except for the increase in proliferation. In total, 258 up-regulated genes and 47 down-regulated genes with an absolute fold change >2 were identified in CAFs co-cultured with MCF7 cell after letrozole treatment. One up-regulated genes (POSTN) and seven down-regulated genes (CCL2, CCL5, CXCL1, IL-8, CXCL5, LEP and NGF) were further validated by real-time PCR. The changes in CCL2 and CXCL1 expression were further confirmed using an automated microscopic imaging-based, high content analysis platform. Although the results need further functional validation, this study is the first to describe the differential tumor-promoting phenotype of CAFs induced by letrozole and the associated gene expression alterations. Most importantly, our data revealed that down-regulation of several secreted factors (CCL2, CCL5, CXCL1 etc.) in CAFs might be partially responsible for the efficacy of letrozole.
authors.affiliation: Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Kaifu
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, People's Republic of China. kanghua@xwh.ccmu.edu.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Hai
authors.affiliation: Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Guohua
authors.initials: G
authors.lastname: Rong
authors.affiliation: Surgery Lab, Xuanwu Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Haichen
authors.initials: H
authors.lastname: Sun
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D000077289:Letrozole; D061986:MCF-7 Cells; D009570:Nitriles / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole
keywords: Aromatase inhibitors; Breast cancer; Carcinoma-associated fibroblasts; Endocrine therapy