PTHrP and breast cancer: more than hypercalcemia and bone metastases

Parathyroid hormone-related protein (PTHrP) causes hypercalcemia in cancer patients. PTHrP is required for normal breast development and has been shown to promote bone metastases from breast cancers. However, whether the protein also contributes to the formation of primary tumors has been unclear. Two recent papers suggest it may. First, a report in Nature Genetics identified the PTHrP locus as a new breast cancer susceptibility gene. Second, a paper in Journal of Clinical Investigation demonstrated that PTHrP promotes tumor growth and metastases in MMTV-PyMT mice. These studies implicate PTHrP in the development and growth of primary breast tumors and underscore the need for further research.


Background
Parathyroid hormone-related protein (PTHrP) -also parathyroid-like hormone (PTHLH) -was discovered as the cause of a common paraneoplastic syndrome, humoral hypercalcemia of malignancy [1,2]. Both the PTHLH and parathyroid hormone genes descended from a common ancestor and both proteins bind and activate the same Gprotein coupled receptor (type 1 PTH/PTHrP receptor). PTHrP is widely expressed in embryos and contributes to the development of many organs, including the breast [1,2]. PTHrP is produced by epithelial cells in the embryonic mammary bud, and the type 1 PTH/PTHrP receptor is expressed by the surrounding mesenchyme. Genetic disruption of either gene results in a failure of mammary development in mice and humans [2]. In the adult virgin breast, PTHrP is produced by myoepithelial cells and its receptor is expressed in the periductal stroma [2,3]. Overexpression of PTHrP in myoepithelial cells inhibits ductal extension, but postnatal disruption of the PTHLH gene in these cells has no eff ect [3]. During lactation, PTHrP is produced by alveolar epithelial cells and is secreted into milk and into the maternal circulation, where it participates in the mobilization of skeletal calcium for milk production [4]. PTHrP thus has important functions in normal breast development and physiology.
PTHrP also contributes to the pathophysiology of breast cancer. PTHrP production by tumor cells in the bone microenvironment has been shown to promote osteoclastic activity and contribute to osteolytic bone metastases [5]. Th e question of PTHrP's function in primary tumors has been less clear. Studies in cultured breast cancer cell lines have reported confl icting eff ects on tumor cell behavior [6,7]. Clinical studies have also shown disparate results; some smaller case series suggest that PTHrP expression predicts more aggressive behavior [8,9], while a large, well-controlled clinical study from Melbourne suggested that PTHrP expression was an independent predictor of a more benign clinical course [10]. Th erefore, while PTHrP's participation in the development of bone metastases has been well established, what eff ects, if any, PTHrP has on the development or progression of primary tumors remained unclear. Now, two recent articles underscore the importance of PTHrP in primary breast cancers and call attention to the need for more studies to clarify the protein's functions in breast cancer biology.

The articles
First, in a recent paper published in Nature Genetics, Ghoussaini and colleagues combined several datasets encom passing 70,000 patients and 68,000 controls in order to perform genome-wide association studies to identify new breast cancer susceptibility loci [11]. One of the three new loci they identifi ed, rs10771399, was in a 300 kb linkage disequilibrium block that contains only one gene, PTHLH.
Second, in work recently published in the Journal of Clinical Investigation, Li and colleagues examined the role of PTHrP expression in an animal model of breast cancer caused by PyMT [12]. Th e authors used the Abstract Parathyroid hormone-related protein (PTHrP) causes hypercalcemia in cancer patients. PTHrP is required for normal breast development and has been shown to promote bone metastases from breast cancers. However, whether the protein also contributes to the formation of primary tumors has been unclear. Two recent papers suggest it may. First, a report in Nature Genetics identifi ed the PTHrP locus as a new breast cancer susceptibility gene. Second, a paper in Journal of Clinical Investigation demonstrated that PTHrP promotes tumor growth and metastases in MMTV-PyMT mice. These studies implicate PTHrP in the development and growth of primary breast tumors and underscore the need for further research.
MMTV-Cre transgene to target the PTHLH gene in mammary epithelial cells, and found that while loss of PTHrP expression did not aff ect tumor incidence, it did dramatically prolong tumor latency, slow tumor growth and reduce metastases. Restraint of tumor growth correlated with reduced proliferation and increased apoptosis, perhaps due to alterations in cyclin D 1 , protein kinase B 1 and 2, and B-cell lymphoma 2 expression. Th e reduction in metastases may have been related to reductions in the expression of CXC chemokine receptor 4 and the inhibition of angio genesis. Finally, the authors developed a blocking anti body to PTHrP and demonstrated that it could inhibit primary tumor growth and lung metastases in a xenograft model. Th ese data suggest that PTHrP powerfully promotes tumor formation in breast cancer.

Discussion
Th e report from Ghoussaini and colleagues focuses atten tion on PTHrP as a potential contributor to breast cancer susceptibility. If the PTHLH gene is confi rmed to be causal in resequencing studies of the rs10771399 locus, then animal studies such as those described by Li and colleagues will be instrumental in understanding how PTHrP might alter disease susceptibility. Together, these two studies raise many interesting questions regard ing the mechanisms by which PTHrP might alter the formation or progression of breast tumors. Perhaps the most perplexing involves the opposite results reported in a similar study by Fleming and colleagues demonstrating that disruption of the PTHrP gene increased the incidence of tumors in MMTV-Neu mice, results consis tent with the clinical study from Australia [10,13]. Th e opposing results of these two transgenic mouse studies highlight an important issue for future research.
Clearly, the molecular context appears to be critical for determining PTHrP's actions. Although both MMTV-Neu and MMTV-PyMT are models of luminal-type cancer, their pathways to transformation vary in important ways, and other molecules also exert diff ering eff ects on tumor formation in these two strains [14,15]. Sorting out why PTHrP has opposite eff ects in these two models will probably provide important clues to understanding the molecular nature of its actions in breast cancer.