Bone Forming Breast Cancer Secreted Factors

About 15% of breast cancer bone metastases are osteoblastic (6). Endothelin-1 (ET-1) is a tumor-secreted peptide with a role in osteoblastic bone metastases (16). ET-1 stimulates osteoblast activity and new bone formation (41). It is secreted by breast cancers and cell lines that produce osteoblastic and mixed bone lesions in mouse models e.g., T47D, MCF-7, ZR75.1, and BT483 (16). Invasive breast tumors express higher ET-1 and ETA receptor than nonneoplastic tissue (42). Patients with breast cancer and lymph node metastases possess higher ET-1 serum levels than patients without lymph node metastases (42). Selective inhibition of the endothelin A receptor decreased osteoblastic metastases formed by ET-1-secreting ZR-75-1 breast cancer cells (16). An ETA receptor antagonist is currently in Phase III clinical trials in men with advanced prostate cancer.

Adrenomedullin (AM) is another secreted peptide that may play a role in osteoblastic breast cancer bone metastases. AM is expressed by human breast cancers and breast cancer cell lines (43). Higher levels of AM tumor peptide expression and AM plasma levels were found in patients with axillary lymph node metastasis compared to patients without axillary lymph node metastasis (43). AM stimulates osteoblast proliferation in vitro and in vivo (44, 45) and induces new bone formation in neonatal mouse calvariae (unpublished data). Overexpression of AM increased lesion formation in a prostate cancer mouse model, while decreasing AM expression decreased bone lesion formation in a lung cancer bone metastasis mouse model (unpublished data). Small molecule inhibitors of AM have been developed (46) that inhibit AM-induced new bone formation in neonatal mouse calvariae (unpublished data). Such agents may reduce breast cancer bone metastases. Like ET-1, AM is a potent stimulator of pain (47). Both peptides may contribute to bone metastasis-associated bone pain, which is a major complication of skeletal metastases.

Tumor-secreted platelet derived growth factor-BB (PDGF-BB) may contribute to osteoblastic metastases. PDGFs are multifunctional cytokines that stimulate both osteoclasts and osteoblasts (48). Breast cancer cells secrete PDGFs and express the PDGF receptor (48, 49). High PDGF plasma and tumor tissue levels are associated with a poorer prognosis for breast cancer, including increased metastases, lower chemotherapeutic response, and lower survival (50, 51). Reduction of PDGF-BB in MCF-7 breast cancer cells that overexpress the neu oncogene decreased osteoblastic bone metastases in nude mice (48). Overexpression of PDGF-BB in MDA-MB-231 breast cancer cells, which normally produce osteolytic lesions, produced osteoblastic lesions (48). Gleevac, a selective inhibitor of PDGF receptor tyrosine kinase activity, decreased growth of breast cancer cells injected into the tibia of mice (49). Such inhibitors could reduce osteoblastic breast cancer bone metastases.

The pro-angiogenic factor connective tissue growth factor (CTGF) is a member of the cysteine-rich CCN protein family and is another breast cancer-secreted factor that stimulates new bone formation (52). Recombinant CTGF increases bone formation and angiogenesis when injected into the femoral marrow cavity of rats (52). CTGF is expressed by breast cancer cells (17, 53). Lower levels of CTGF were detected in breast tumors compared to normal tissues (54). Low CTGF levels are associated with a poor prognosis, metastasis, local recurrence, and mortality (54). However, CTGF expression at sites of bone metastases has not been reported. CTGF is a member of the bone metastatic gene profile identified by Kang et al. in 2003 (17). Overexpressing CTGF alone did not increase bone metastases formed by MDA-MB-231 in mice. However, over-expressing IL-11, osteopontin, and CTGF together significantly increased the rate and incidence of bone metastases (17). CTGF neutralizing antibodies decreased osteolytic lesions formed by MDA-MB-231 cells in mice (55). Thus, CTGF appears to play an important role in bone metastases. The bone microenvironment may induce an increase in CTGF expression.

Another member of the CCN family that stimulates osteoblasts, cysteine-rich protein 61 (Cyr61), may also play a role in bone metastases (56, 57). Breast cancer tumor tissues expressed higher Cyr61 levels than normal breast tissues (54). High Cyr61 levels were associated with poor prognosis, nodal involvement, and metastatic disease in breast cancer patients (54). It was recently found that a bone-metastatic variant of MDA-MB-231 cells showed increased expression of Cyr61, CTGF, and ET-1, as well as the osteolytic factors IL-11 and IL-8 (58).

PTHrP also may play a role in osteoblastic metastases (59). PTHrP expression is commonly found in prostate cancer cells that produce osteoblastic metastases (60). PTHrP can be cleaved at residue 23 by the serine proteinase prostate-specific antigen (PSA) (59) that is commonly expressed by breast cancers (61, 62). The resulting PTHrP fragment does not activate the PTH/PTHrP receptor. PTHrP fragments 1-16 and 1-23 stimulate new bone formation in ex vivo calvarial organ cultures, and this stimulation was blocked by an ETAR antagonist, ABT-627, suggesting that PTHrP fragments may stimulate new bone formation through the endothelin A receptor (59). However, Langlois et al. (2005) were unable to show binding of PTHrP 1-16 and 1-23 to the ETA or ETB receptor (60). Proteolysis may convert PTHrP from an osteolytic to an osteoblastic factor. Therefore, neutralizing PTHrP may also be beneficial for osteoblastic bone metastases, while ETA receptor antagonists may be effective against tumors that make PTHrP fragments but are ET-1-negative.

The bone morphogenetic proteins (BMPs) are a family of growth factors that stimulate bone formation and are part of the TGFp super-family (63). Breast cancer cells express BMPs and BMP receptors (64). Different BMPs may have both growth inhibitory and stimulatory effects on breast cancer cells (65, 66). Increased expression of the bone morpho-genetic protein receptor IB is associated with increased tumor grade, proliferation, cytogenetic instability, and poor prognosis of estrogen receptor-positive breast carcinomas (67). Overexpression of BMP-2 in MCF-7 breast cancer cells increased the invasive ability of these cells in vitro and enhanced estrogen-independent growth in a xenograft mouse model (68). Overexpression of the BMP antagonist, noggin, in PC3 and LAPC-9 prostate cancer cells decreased osteolytic and osteoblastic lesions, respectively, produced by the prostate cancer cells after injection into the tibia of SCID mice (69, 70).

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