Cellular calcium dynamics in lactation and breast cancer: from physiology to pathology

Abstract

Breast cancer is the second leading cause of cancer mortality in women, estimated at nearly 40,000 deaths and more than 230,000 new cases diagnosed in the U.S. this year alone. One of the defining characteristics of breast cancer is the radiographic presence of microcalcifications. These palpable mineral precipitates are commonly found in the breast after formation of a tumor. Since free Ca(2+) plays a crucial role as a second messenger inside cells, we hypothesize that these chelated precipitates may be a result of dysregulated Ca(2+) secretion associated with tumorigenesis. Transient and sustained elevations of intracellular Ca(2+) regulate cell proliferation, apoptosis and cell migration, and offer numerous therapeutic possibilities in controlling tumor growth and metastasis. During lactation, a developmentally determined program of gene expression controls the massive transcellular mobilization of Ca(2+) from the blood into milk by the coordinated action of calcium transporters, including pumps, channels, sensors and buffers, in a functional module that we term CALTRANS. Here we assess the evidence implicating genes that regulate free and buffered Ca(2+) in normal breast epithelium and cancer cells and discuss mechanisms that are likely to contribute to the pathological characteristics of breast cancer.

Keywords: SPCA2; breast cancer; lactation; mammary epithelium; secretory pathway.

Fig. 1.

Multiple modes of Ca²⁺ entry occur in mammary epithelial cells. Left: store-operated mechanisms are triggered by aggregation of STIM proteins that sense luminal Ca²⁺ in endoplasmic reticulum (ER) stores. Direct interaction with plasma membrane Orai1 channels elicits Ca²⁺ entry, localized increase in Ca²⁺_cyt, and refilling of stores by the sarcoendoplasmic reticulum Ca²⁺-ATPase (SERCA) pump. SOCE, store-operated Ca²⁺ entry. Right: store-independent mechanisms include a direct interaction between the secretory pathway Ca²⁺-ATPase-2 (SPCA2) pump located in Golgi-derived vesicles (GDV) and Orai1 channels resulting in Ca²⁺ influx and potential refilling of Golgi stores by fusion of Ca²⁺-loaded vesicles. Red arrows indicate ATP utilization by the SERCA and SPCA2 pumps; dotted lines show movement of STIM or SPCA2, required for Ca²⁺ entry mechanisms. SICE, store-independent Ca²⁺ entry.

Fig. 2.

Calcium movement by the calcium transporter (CALTRANS) module during lactation. During lactation, the coordinated induction of milk proteins (β/κ-casein) and calcium pumps [SPCA2, plasma membrane Ca²⁺-ATPase-2 (PMCA2), SERCA2] and channels (TRPC6, Orai1) ensures the efficient transcytosis of Ca²⁺ ions from the blood (basolateral side) to the lumen (apical side) of the mammary gland. Interaction between SPCA2, localized to Golgi-derived vesicles, and Orai1 (and possibly TRPC6) elicits Ca²⁺ influx at the basal membrane. Ca²⁺ forms complexes with casein and anions within secretory vesicles, which fuse with the apical membrane. Direct pumping of Ca²⁺ ions into the lumen by the PMCA2 pump also elevates calcium to total levels of 40–60 mM (ionized and bound) in milk.

Fig. 3.

Distinct modes of calcium remodeling in cancer. A: we hypothesize that in rapidly proliferating, primary tumors intracellular Ca²⁺ stores are replete due to elevated expression of SERCA2 and SPCA2, and Ca²⁺ entry occurs by SICE. B: in cancer cells that have undergone epithelial to mesenchymal transition, ER Ca²⁺ stores are released under stimulation by increased GPCR signaling at the plasma membrane, and migration requires SOCE.