Calcium Metabolism and Breast Cancer: Echoes of Lactation?

Abstract

Lactation requires a series of adaptations in maternal calcium and bone metabolism to ensure a steady supply of calcium to the lactating mammary gland. The alterations in systemic metabolism are accompanied by alterations in the expression of calcium receptors, channels, binding proteins, pumps and transporters in mammary epithelial cells to increase the uptake of calcium from the extracellular fluid and to transport it into milk. Intracellular calcium regulates signaling pathways that mediate changes in cell proliferation, differentiation and death and many of the molecules involved in supporting and coordinating calcium secretion into milk are re-expressed and redeployed to support malignant behavior in breast cancer cells. In this article, we review adaptations of systemic calcium homeostasis during lactation, as well as the mechanisms of milk calcium transport. We then discuss how reactivation of these pathways contributes to the pathophysiology of breast cancer.

Keywords: Bone; Breast Cancer; Calcium-sensing receptor; Lactation; Mammary gland; Parathyroid hormone-related protein.

Figure 1.. CaSR and PTHrP feedback loop in lactation and in breast cancer.

(A) Circulating PTHrP acts on the kidney and on the bone to stimulate calcium reabsorption and bone resorption, respectively. In the bone, PTHrP acts on osteoblasts (Ob) to produce RANKL that induces pre-osteoclast (preOcl) differentiation to osteoclast (Ocl) and Ocl bone resorption on one hand and osteocyte (Oc) osteolysis on the other. This, liberates skeletal calcium stores which are transported via the bloodstream to the lactating mammary gland, where calcium activates the CaSR on the basolateral surface to promote calcium entry into the cells, stimulate PMCA2 mediated calcium transport into milk and to inhibit PTHrP expression, therefore establishing a negative feedback loop. (B) In breast cancer cells, high local calcium concentrations activate the CaSR leading to increased PTHrP production. PTHrP secretion induces RANKL secretion by Ob, thereby driving more osteolysis and releasing calcium from the bone matrix that, in turn, stimulates the CaSR. Activation of the CaSR promotes breast cancer cell proliferation and enhances cell survival by stimulating intracrine and paracrine actions of PTHrP. The CaSR may also increase PMCA2 calcium pump activity to protect the breast cancer cells from calcium-mediated apoptosis. As a result, activation of the CaSR in breast cancer cells facilitates a feed-forward, vicious cycle of bone resorption, tumor growth and osteolysis.

Figure 2.. CALTRANS model of calcium transport across mammary epithelial cells into milk.

The 4 steps of the model 1) Calcium Entry, 2) Calcium Sequestration from cytosol, 3) Calcium packaging into casein micelles and 4) Caclium transport across the apical membrane are detailed in the text. Adapted from Cross et. Al, ref. .

Figure 3.. HER2 signaling complex in breast cancer cells.

ATP2b2 (PMCA2) gene expression is reactivated in HER2-positive breast cancer cells and PMCA2 becomes an integral part of a multiprotein and lipid signaling complex that is required for the membrane retention of actively signaling HER2. Adapted from Jeong et. al., ref .