title: Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer.
abstract: Increased collagen expression in tumors is associated with increased risk of metastasis, and triple-negative breast cancer (TNBC) has the highest propensity to develop distant metastases when there is evidence of central fibrosis. Transforming growth factor-β (TGF-β) ligands regulated by cancer-associated fibroblasts (CAFs) promote accumulation of fibrosis and cancer progression. In the present study, we have evaluated TNBC tumors with enhanced collagen to determine whether we can reduce metastasis by targeting the CAFs with Pirfenidone (PFD), an anti-fibrotic agent as well as a TGF-β antagonist. In patient-derived xenograft models, TNBC tumors exhibited accumulated collagen and activated TGF-β signaling, and developed lung metastasis. Next, primary CAFs were established from 4T1 TNBC homograft tumors, TNBC xenograft tumors and tumor specimens of breast cancer patients. CAFs promoted primary tumor growth with more fibrosis and TGF-β activation and lung metastasis in 4T1 mouse model. We then examined the effects of PFD in vitro and in vivo. We found that PFD had inhibitory effects on cell viability and collagen production of CAFs in 2D culture. Furthermore, CAFs enhanced tumor growth and PFD inhibited the tumor growth induced by CAFs by causing apoptosis in the 3D co-culture assay of 4T1 tumor cells and CAFs. In vivo, PFD alone inhibited tumor fibrosis and TGF-β signaling but did not inhibit tumor growth and lung metastasis. However, PFD inhibited tumor growth and lung metastasis synergistically in combination with doxorubicin. Thus, PFD has great potential for a novel clinically applicable TNBC therapy that targets tumor-stromal interaction.
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA, USA.|Present address: Division of Breast Oncology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Takai
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA, USA.|Present address: St. George's University School of Medicine, Grenada.
authors.forename: Annie
authors.initials: A
authors.lastname: Le
authors.affiliation: Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, CA, USA.
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA, USA.
authors.forename: Zena
authors.initials: Z
authors.lastname: Werb
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D011728:Pyridones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011728:Pyridones; D016212:Transforming Growth Factor beta; D003094:Collagen; C093844:pirfenidone
keywords: cancer-associated fibroblast; fibrosis; pirfenidone; transforming growth factor-β; triple-negative breast cancer