ABSTRACT
BACKGROUND: Metastasis to the bone is a deleterious aspect of breast cancer and is a preferred site that results in bone loss. Hormones such as prolactin (PRL) have not yet been studied for their role in modulating the secondary tumor bone microenvironment. METHODS: We used quantitative immunohistochemistry with 134 samples of human primary breast cancer and 17 matched primary breast cancers and bone metastases. A Cox proportional hazards regression model was fitted to evaluate the associations between high prolactin receptor (PRLR) expression and time to bone metastasis, adjusting for estrogen receptor status, lymph node status, and chemotherapy status. We assessed osteoclast differentiation, osteoclast size, and measured pit formation in dentine slices. Statistical tests were two-sided. RESULTS: High PRLR expression in the primary breast tumor was associated with a shorter time to metastasis that includes bone (PRLRAQUA Max-per 100 unit hazard ratio = 1.04, 95% confidence interval = 1.00 to 1.07, P = .03). We observed the PRLR in rare samples of bone metastases and matched primary breast cancer. PRL treatment of breast cancer cells induced osteoclast differentiation and bone lysis via secreted factors and was abrogated by a PRLR antagonist (delta1-9-G129R-hPRL). We demonstrated that sonic hedgehog is a PRL-regulated cytokine in breast cancer cells and part of the mechanism that induces osteoclast differentiation. CONCLUSIONS: Our evidence indicates that PRL-PRLR can escalate the impact of breast cancer on bone metastasis and that the presence of the PRLR in the tumor microenvironment of breast cancer bone metastasis has the potential to modulate the microenvironment to induce lytic osteoclast formation.
Subject(s)
Bone Neoplasms/metabolism , Breast Neoplasms/metabolism , Cell Differentiation , Hedgehog Proteins/metabolism , Osteoclasts/metabolism , Osteoclasts/pathology , Prolactin/metabolism , Receptors, Prolactin/metabolism , Signal Transduction , Adult , Aged , Bone Neoplasms/chemistry , Bone Neoplasms/secondary , Breast Neoplasms/chemistry , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Middle Aged , Neoplastic Cells, Circulating/chemistry , Odds Ratio , Prolactin/analysis , Proportional Hazards Models , Receptors, Prolactin/analysis , Time Factors , Tissue Array AnalysisABSTRACT
Murine models for the study of lung cancer have historically been the backbone of preliminary preclinical data to support early human clinical trials. However, the availability of multiple experimental systems leads to debate concerning which model, if any, is best suited for a particular therapeutic strategy. It is imperative that these models accurately predict clinical benefit of therapy. This review provides an overview of the current murine models used to study lung cancer and the advantages and limitations of each model, as well as a retrospective evaluation of the uses of each model with respect to accuracy in predicting clinical benefit of therapy. A better understanding of murine models and their uses, as well as their limitations may aid future research concerning the development and implementation of new targeted therapies and chemotherapeutic agents for lung cancer.
Subject(s)
Disease Models, Animal , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Animals , Antineoplastic Agents/therapeutic use , Clinical Trials as Topic , Humans , Lung Neoplasms/genetics , MiceABSTRACT
The preferential metastasis of breast cancer cells to bone is a complex set of events including homing and preferential growth which may include unique factors produced by bone cells in the immediate microenvironment. In this study, we evaluated the suitability of bone cells derived from orthoplastic surgeries for use in an in vitro co-culture system representing a model of the bone microenvironment. Using a limiting dilution assay we determined the relative survival and proliferation potentials of breast cancer cell lines co-cultured on bone-derived cells or on Hs68 fibroblasts. The comparison of bone and skin fibroblastic substrata indicates that MCF-7 cells preferentially survive and grow in a bone microenvironment (P < 0.001). Overall, we show that bone-derived cells enhance survival, proliferation, and migration of breast cancer cells, where migration is in part mediated by bone cell-produced osteopontin. Our in vitro co-culture model system provides a robust cost-effective method to study the various factors that mediate cancer/bone-derived cell interactions.
