Calcium-Sensing Receptor Tumor Expression and Lethal Prostate Cancer Progression.
Prostate cancer metastases preferentially target bone, and the calcium-sensing receptor (CaSR) may play a role in promoting this metastatic progression.



We evaluated the association of prostate tumor CaSR expression with lethal prostate cancer.



A validated CaSR immunohistochemistry assay was performed on tumor tissue microarrays. Vitamin D receptor (VDR) expression and phosphatase and tensin homolog tumor status were previously assessed in a subset of cases by immunohistochemistry. Cox proportional hazards models adjusting for age and body mass index at diagnosis, Gleason grade, and pathological tumor node metastasis stage were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of CaSR expression with lethal prostate cancer.



The investigation was conducted in the Health Professionals Follow-up Study and Physicians' Health Study.



We studied 1241 incident prostate cancer cases diagnosed between 1983 and 2009.



Participants were followed up or cancer-specific mortality or development of metastatic disease.



On average, men were followed up 13.6 years, during which there were 83 lethal events. High CaSR expression was associated with lethal prostate cancer independent of clinical and pathological variables (HR 2.0; 95% CI 1.2-3.3). Additionally, there was evidence of effect modification by VDR expression; CaSR was associated with lethal progression among men with low tumor VDR expression (HR 3.2; 95% CI 1.4-7.3) but not in cases with high tumor VDR expression (HR 0.8; 95% CI 0.2-3.0).



Tumor CaSR expression is associated with an increased risk of lethal prostate cancer, particularly in tumors with low VDR expression. These results support further investigating the mechanism linking CaSR with metastases.
Departments of Epidemiology (T.U.A., K.M.W., E.N., H.D.S., E.G., L.A.M., I.M.S.) and Department of Nutrition (E.G.), Harvard T. H. Chan School of Public Health, Department of Medical Oncology (R.L., M.L.), Dana-Farber Cancer Institute, Divisions of Preventive Medicine (H.D.S.), and Channing Division of Network Medicine (K.M.W., E.G., L.A.M.), Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115; Department of Histopathology Research (N.T., S.F.), Trinity College, Dublin 8, Ireland; and Public Health Sciences Division (I.M.S.), Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
Thomas U
TU
Ahearn
Departments of Epidemiology (T.U.A., K.M.W., E.N., H.D.S., E.G., L.A.M., I.M.S.) and Department of Nutrition (E.G.), Harvard T. H. Chan School of Public Health, Department of Medical Oncology (R.L., M.L.), Dana-Farber Cancer Institute, Divisions of Preventive Medicine (H.D.S.), and Channing Division of Network Medicine (K.M.W., E.G., L.A.M.), Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115; Department of Histopathology Research (N.T., S.F.), Trinity College, Dublin 8, Ireland; and Public Health Sciences Division (I.M.S.), Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
Nairi
N
Tchrakian
Departments of Epidemiology (T.U.A., K.M.W., E.N., H.D.S., E.G., L.A.M., I.M.S.) and Department of Nutrition (E.G.), Harvard T. H. Chan School of Public Health, Department of Medical Oncology (R.L., M.L.), Dana-Farber Cancer Institute, Divisions of Preventive Medicine (H.D.S.), and Channing Division of Network Medicine (K.M.W., E.G., L.A.M.), Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115; Department of Histopathology Research (N.T., S.F.), Trinity College, Dublin 8, Ireland; and Public Health Sciences Division (I.M.S.), Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
Kathryn M
KM
Wilson
Departments of Epidemiology (T.U.A., K.M.W., E.N., H.D.S., E.G., L.A.M., I.M.S.) and Department of Nutrition (E.G.), Harvard T. H. Chan School of Public Health, Department of Medical Oncology (R.L., M.L.), Dana-Farber Cancer Institute, Divisions of Preventive Medicine (H.D.S.), and Channing Division of Network Medicine (K.M.W., E.G., L.A.M.), Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115; Department of Histopathology Research (N.T., S.F.), Trinity College, Dublin 8, Ireland; and Public Health Sciences Division (I.M.S.), Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
Rosina
R
Lis
Departments of Epidemiology (T.U.A., K.M.W., E.N., H.D.S., E.G., L.A.M., I.M.S.) and Department of Nutrition (E.G.), Harvard T. H. Chan School of Public Health, Department of Medical Oncology (R.L., M.L.), Dana-Farber Cancer Institute, Divisions of Preventive Medicine (H.D.S.), and Channing Division of Network Medicine (K.M.W., E.G., L.A.M.), Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115; Department of Histopathology Research (N.T., S.F.), Trinity College, Dublin 8, Ireland; and Public Health Sciences Division (I.M.S.), Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
Elizabeth
E
Nuttall
Departments of Epidemiology (T.U.A., K.M.W., E.N., H.D.S., E.G., L.A.M., I.M.S.) and Department of Nutrition (E.G.), Harvard T. H. Chan School of Public Health, Department of Medical Oncology (R.L., M.L.), Dana-Farber Cancer Institute, Divisions of Preventive Medicine (H.D.S.), and Channing Division of Network Medicine (K.M.W., E.G., L.A.M.), Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115; Department of Histopathology Research (N.T., S.F.), Trinity College, Dublin 8, Ireland; and Public Health Sciences Division (I.M.S.), Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
Howard D
HD
Sesso
Departments of Epidemiology (T.U.A., K.M.W., E.N., H.D.S., E.G., L.A.M., I.M.S.) and Department of Nutrition (E.G.), Harvard T. H. Chan School of Public Health, Department of Medical Oncology (R.L., M.L.), Dana-Farber Cancer Institute, Divisions of Preventive Medicine (H.D.S.), and Channing Division of Network Medicine (K.M.W., E.G., L.A.M.), Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115; Department of Histopathology Research (N.T., S.F.), Trinity College, Dublin 8, Ireland; and Public Health Sciences Division (I.M.S.), Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
Massimo
M
Loda
Departments of Epidemiology (T.U.A., K.M.W., E.N., H.D.S., E.G., L.A.M., I.M.S.) and Department of Nutrition (E.G.), Harvard T. H. Chan School of Public Health, Department of Medical Oncology (R.L., M.L.), Dana-Farber Cancer Institute, Divisions of Preventive Medicine (H.D.S.), and Channing Division of Network Medicine (K.M.W., E.G., L.A.M.), Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115; Department of Histopathology Research (N.T., S.F.), Trinity College, Dublin 8, Ireland; and Public Health Sciences Division (I.M.S.), Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
Edward
E
Giovannucci
Departments of Epidemiology (T.U.A., K.M.W., E.N., H.D.S., E.G., L.A.M., I.M.S.) and Department of Nutrition (E.G.), Harvard T. H. Chan School of Public Health, Department of Medical Oncology (R.L., M.L.), Dana-Farber Cancer Institute, Divisions of Preventive Medicine (H.D.S.), and Channing Division of Network Medicine (K.M.W., E.G., L.A.M.), Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115; Department of Histopathology Research (N.T., S.F.), Trinity College, Dublin 8, Ireland; and Public Health Sciences Division (I.M.S.), Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
Lorelei A
LA
Mucci
Departments of Epidemiology (T.U.A., K.M.W., E.N., H.D.S., E.G., L.A.M., I.M.S.) and Department of Nutrition (E.G.), Harvard T. H. Chan School of Public Health, Department of Medical Oncology (R.L., M.L.), Dana-Farber Cancer Institute, Divisions of Preventive Medicine (H.D.S.), and Channing Division of Network Medicine (K.M.W., E.G., L.A.M.), Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115; Department of Histopathology Research (N.T., S.F.), Trinity College, Dublin 8, Ireland; and Public Health Sciences Division (I.M.S.), Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
Stephen
S
Finn
Departments of Epidemiology (T.U.A., K.M.W., E.N., H.D.S., E.G., L.A.M., I.M.S.) and Department of Nutrition (E.G.), Harvard T. H. Chan School of Public Health, Department of Medical Oncology (R.L., M.L.), Dana-Farber Cancer Institute, Divisions of Preventive Medicine (H.D.S.), and Channing Division of Network Medicine (K.M.W., E.G., L.A.M.), Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115; Department of Histopathology Research (N.T., S.F.), Trinity College, Dublin 8, Ireland; and Public Health Sciences Division (I.M.S.), Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
Irene M
IM
Shui
D000368:Aged; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D018167:Receptors, Calcitriol / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*
D018167:Receptors, Calcitriol; D044169:Receptors, Calcium-Sensing