- High serum calcium has been found to be associated with aggressive
breast cancer in premenopausal women and larger tumors in postmenopausal
- Current study suggests possible association between mutations in
the calcium sensing receptor (CaSR) gene and high serum calcium levels in
a set of breast cancer patients.
Mutations in the CaSR gene may be at
least partially responsible for high serum calcium levels in breast cancer
patients which in turn lead to more aggressive disease and poorer prognosis,
according to a recent retrospective case
control study at the Vanderbilt University
. The findings of the study
appear in the Biomed Central Cancer
journal in August 2017.
Reasons for High Serum Calcium Levels in Breast
Cancer - Aim of Study
Earlier studies have shown that breast
cancer tends to be more aggressive in
premenopausal women and women of African
‘Calcium induced hypercalcemia (CIH) leading to aggressive and/or larger breast cancers in some women may at least be partly due to inactivating mutations in the CaSR gene.’
The reasons for this are poorly
understood, but one possible factor could be cancer induced hypercalcemia
(CIH) which invariably occurs in end stage
aggressive and metastatic disease. Also calcium levels have been found to be
high in women with untreated breast cancer. Additionally high serum calcium
levels have been found to be associated with a more aggressive course in
younger (premenopausal) and/or overweight women.
The reasons for the high serum calcium
levels and associated poor outcome in breast cancer remain unclear and the current study aimed to determine whether
alterations in the CaSR gene leading to a reduced calcium sensitivity could
contribute to the CIH
in these women.
of The Study
This was a retrospective case-control study that studied 199 breast cancer and 384
age matched controls
. Parameters assessed included mean circulating calcium levels and the distribution of two
inactivating calcium sensing receptor (CaSR) mutations
to determine whether
these SNPs are associated with circulating calcium in control subjects and BC
cases. Findings of The Study
- Mean serum calcium levels were significantly higher in breast cancer
patients than controls.
- Among the control group, serum calcium
levels were significantly more in
African American women compared to Caucasian women.
- However in the breast cancer group,
circulating calcium levels did not differ markedly between African
American and Caucasian women, suggesting that CIH is not dependent on race.
- Mean circulating calcium levels were significantly
higher in all subjects (cases and controls) who expressed the variant of the CASR gene at the
rs1801725 SNP, but NOT
with variants of the CaSR at the rs1801726 SNP (another allele).
- Another notable observation was high calcium levels in African women
was not associated with either of the CaSR polymorphisms. But
Caucasian women expressing the variant of the CASR gene at the
rs1801725 SNP showed significantly higher serum calcium levels.
- In breast cancer patients, inactivating mutations of the CASR gene
at the rs1801725 SNP were significantly associated with circulating
calcium while no such association was noted with inactivating
mutations at the rs1801726 SNP.
The findings suggest that CASR variants at the rs1801725 SNP could
contribute to the development of breast cancer-induced hypercalcemia
the subsequent high circulating calcium associated progression of BC into
aggressive and bigger tumors in nearly 20% of women with mutations at the
Induced Hypercalcemia In Breast Cancer
Cancer induced hypercalcemia is often
seen in advanced breast cancer and in patients with bony metastasis. Increases
in serum calcium are not detected or are very mild with no clinical
significance. However, these mild increases may promote disease progression and
spread by activating CaSR mutations or other calcium dependent cancer pathways.
The forces behind this cancer induced
hypercalcemia (CIH) are not entirely clear.
From The Study
Scope of This Study
- The study team believes that the hypercalcemia seen in breast cancer
may be due to a combination of CaSR inactivating mutations and tumor
cell derived osteolytic (dissolve bone) factors.
- Higher baseline calcium levels found in women of African descent may
contribute to the more aggressive disease seen in these women.
- The high serum calcium levels in
breast cancer women of African descent were not found to be related to
CaSR mutations during this study. The team believes that other mechanisms may be at play
causing hypercalcemia in African women with breast cancer, which
however could not be satisfactorily evaluated in this study due to lack of
Based on this study, future research could focus on the
following factors to gain better insight and clarity in the processes underlying
- Studying the role of elevated
calcium levels in larger multi-center studies
- The role of CaSR gene mutations in
influencing the prognosis in breast carcinoma women
- Modifying the function of the CaSR
by pharmacological inhibition of its activity e.g. using calcilytic agents
has been found to decrease cancer proliferation and spread. Newer treatment options focusing on
this pathway may be explored in breast cancer women having hypercalcemia.
- Li Wang, Sarrah E. Widatalla, Diva S. Whalen, Josiah Ochieng and Amos M. Sakwe. Association of calcium sensing receptor polymorphisms at rs1801725 with circulating calcium in breast cancer patients. BMC Cancer DOI: https:doi.org/10.1186/s12885-017-3502-3