Dataset Information

The CaSR in Pathogenesis of Breast Cancer: A New Target for Early Stage Bone Metastases.

ABSTRACT: The Ca2+-sensing receptor (CaSR) is a class-C G protein-coupled receptor which plays a pivotal role in calciotropic processes, primarily in regulating parathyroid hormone secretion to maintain systemic calcium homeostasis. Among its non-calciotropic roles, where the CaSR sits at the intersection of myriad processes, it has steadily garnered attention as an oncogene or tumor suppressor in different organs. In maternal breast tissues the CaSR promotes lactation but in breast cancer it acts as an oncoprotein and has been shown to drive the pathogenesis of skeletal metastases from breast cancer. Even though research has made great strides in treating primary breast cancer, there is an unmet need when it comes to treatment of metastatic breast cancer. This review focuses on how the CaSR leads to the pathogenesis of breast cancer by contrasting its role in healthy tissues and tumorigenesis, and by drawing brief parallels with the tissues where it has been implicated as an oncogene. A class of compounds called calcilytics, which are CaSR antagonists, have also been surveyed in the instances where they have been used to target the receptor in cancerous tissues and constitute a proof of principle for repurposing them. Current clinical therapies for treating bone metastases from breast cancer are limited to targeting osteoclasts and a deeper understanding of the CaSR signaling nexus in this context can bolster them or lead to novel therapeutic interventions.

SUBMITTER: Das S

PROVIDER: S-EPMC7013091 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The CaSR in Pathogenesis of Breast Cancer: A New Target for Early Stage Bone Metastases.

Das Souvik S Clézardin Philippe P Kamel Said S Brazier Michel M Mentaverri Romuald R

Frontiers in oncology 20200205

The Ca<sup>2+</sup>-sensing receptor (CaSR) is a class-C G protein-coupled receptor which plays a pivotal role in calciotropic processes, primarily in regulating parathyroid hormone secretion to maintain systemic calcium homeostasis. Among its non-calciotropic roles, where the CaSR sits at the intersection of myriad processes, it has steadily garnered attention as an oncogene or tumor suppressor in different organs. In maternal breast tissues the CaSR promotes lactation but in breast cancer it a ...[more]

PMID: 32117726

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Project description:ContextImmunochemical staining of sentinel lymph nodes (SLNs) and bone marrow identifies breast cancer metastases not seen with routine pathological or clinical examination.ObjectiveTo determine the association between survival and metastases detected by immunochemical staining of SLNs and bone marrow specimens from patients with early-stage breast cancer.Design, setting, and patientsFrom May 1999 to May 2003, 126 sites in the American College of Surgeons Oncology Group Z0010 trial enrolled women with clinical T1 to T2N0M0 invasive breast carcinoma in a prospective observational study.InterventionsAll 5210 patients underwent breast-conserving surgery and SLN dissection. Bone marrow aspiration at the time of operation was initially optional and subsequently mandatory (March 2001). Sentinel lymph node specimens (hematoxylin-eosin negative) and bone marrow specimens were sent to a central laboratory for immunochemical staining; treating clinicians were blinded to results.Main outcome measuresOverall survival (primary end point) and disease-free survival (a secondary end point).ResultsOf 5119 SLN specimens (98.3%), 3904 (76.3%) were tumor-negative by hematoxylin-eosin staining. Of 3326 SLN specimens examined by immunohistochemistry, 349 (10.5%) were positive for tumor. Of 3413 bone marrow specimens examined by immunocytochemistry, 104 (3.0%) were positive for tumors. At a median follow-up of 6.3 years (through April 2010), 435 patients had died and 376 had disease recurrence. Immunohistochemical evidence of SLN metastases was not significantly associated with overall survival (5-year rates: 95.7%; 95% confidence interval [CI], 95.0%-96.5% for immunohistochemical negative and 95.1%; 95% CI, 92.7%-97.5% for immunohistochemical positive disease; P = .64; unadjusted hazard ratio [HR], 0.90; 95% CI, 0.59-1.39; P = .64). Bone marrow metastases were associated with decreased overall survival (unadjusted HR for mortality, 1.94; 95% CI, 1.02-3.67; P = .04), but neither immunohistochemical evidence of tumor in SLNs (adjusted HR, 0.88; 95% CI, 0.45-1.71; P = .70) nor immunocytochemical evidence of tumor in bone marrow (adjusted HR, 1.83; 95% CI, 0.79-4.26; P = .15) was statistically significant on multivariable analysis.ConclusionAmong women receiving breast-conserving therapy and SLN dissection, immunohistochemical evidence of SLN metastasis was not associated with overall survival over a median of 6.3 years, whereas occult bone marrow metastasis, although rare, was associated with decreased survival.Trial registrationclinicaltrials.gov Identifier: NCT00003854.

Project description:Bone is the most common site of breast cancer distant metastasis, affecting 50-70 % of patients who develop metastatic disease. Despite decades of informative research, the effective prevention, prediction and treatment of these lesions remains elusive. The Breast Cancer to Bone (B2B) Metastases Research Program consists of a prospective cohort of incident breast cancer patients and four sub-projects that are investigating priority areas in breast cancer bone metastases. These include the impact of lifestyle factors and inflammation on risk of bone metastases, the gene expression features of the primary tumour, the potential role for metabolomics in early detection of bone metastatic disease and the signalling pathways that drive the metastatic lesions in the bone.The B2B Research Program is enrolling a prospective cohort of 600 newly diagnosed, incident, stage I-IIIc breast cancer survivors in Alberta, Canada over a five year period. At baseline, pre-treatment/surgery blood samples are collected and detailed epidemiologic data is collected by in-person interview and self-administered questionnaires. Additional self-administered questionnaires and blood samples are completed at specified follow-up intervals (24, 48 and 72 months). Vital status is obtained prior to each follow-up through record linkages with the Alberta Cancer Registry. Recurrences are identified through medical chart abstractions. Each of the four projects applies specific methods and analyses to assess the impact of serum vitamin D and cytokine concentrations, tumour transcript and protein expression, serum metabolomic profiles and in vitro cell signalling on breast cancer bone metastases.The B2B Research Program will address key issues in breast cancer bone metastases including the association between lifestyle factors (particularly a comprehensive assessment of vitamin D status) inflammation and bone metastases, the significance or primary tumour gene expression in tissue tropism, the potential of metabolomic profiles for risk assessment and early detection and the signalling pathways controlling the metastatic tumour microenvironment. There is substantial synergy between the four projects and it is hoped that this integrated program of research will advance our understanding of key aspects of bone metastases from breast cancer to improve the prevention, prediction, detection, and treatment of these lesions.

Dataset Information

The CaSR in Pathogenesis of Breast Cancer: A New Target for Early Stage Bone Metastases.

Publications

The CaSR in Pathogenesis of Breast Cancer: A New Target for Early Stage Bone Metastases.

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