Abstract
An important component of breast milk, calcium also appears as radiographically prominent microcalcifications in breast tissue that are often the earliest sign of malignancy. Ionic Ca(2+) is a universal second messenger that controls a wide swathe of effector pathways integral to gene transcription, cell cycle control, differentiation, proliferation, cell migration, and apoptosis. Whereas prolonged elevation in resting Ca(2+) levels drives proliferation to initiate and sustain tumor growth, depletion of calcium stores and attenuation of calcium influx pathways underlies tumor chemoresistance and evasion of apoptosis. This paradox of Ca(2+) homeostasis highlights the challenge of targeting Ca(2+) signaling pathways for breast cancer therapy. Furthermore, breast cancer is a heterogeneous disease classified into distinct subtypes based on tumor origin, stage of invasiveness and hormone receptor status. Classification is important for tailoring treatment, and in predicting clinical outcome or response to chemotherapy. There have been numerous reports of dysregulated expression, localization or activity of Ca(2+) channels, regulators and pumps in breast cancer. An important aspect of these alterations is that they are specific to breast cancer subtype, as exemplified by a reciprocal switch in secretory pathway Ca(2+)-ATPase isoforms SPCA1 and SPCA2 depending on receptor status. In this review, we discuss the current knowledge of subtype specific changes in calcium channels and pumps, with a focus on functional insights that may inform new opportunities for breast cancer therapy.