New concepts of breast cell communication to bone

• Breast epithelium becomes an endocrine tissue during lactation, secreting PTHrP to mobilize bone mineral for export into the milk.
• PTHrP expression and secretion are driven by serotonin, synthesized in the breast epithelium during lactation.
• Mammary gland expression of the calcium-sensing receptor integrates calcium homeostasis of the mother–infant dyad during lactation by inducing calcium export via PMCA2 and mediating feedback inhibition of PTHrP.
• Osteocytes, rather than osteoblasts, may play an important role by responding to PTHrP and mediating the mobilization of bone calcium.

Lactation is the most extreme case of normal physiological bone loss during a lifetime, and breast cancers have a strong tendency to metastasize to bone. In both the physiological and pathological circumstances, parathyroid hormone-related peptide (PTHrP) plays a central role. Until recently there were no regulatory mechanisms to explain the induction of endocrine PTHrP secretion from breast cells during lactation. The mammary epithelium possesses a local serotonin signaling system which drives PTHrP expression during lactation and in breast cancer cells. The mammary gland serotonin system is highly induced in response to alveolar dilation due to milk secretion. Discovery of serotonergic control of PTHrP suggests that it may be possible to manipulate the breast-to-bone axis by targeting serotonin signaling.