Expression of Bone Matrix Proteins in Human Breast Cancer: Potential Roles in Microcalcification Formation and in the Genesis of Bone Metastases

in Bulletin du Cancer (1997), 84(1), 17-24

The skeleton is the privileged target of metastatic human breast cancer cells. Bone metastases are indeed found in virtually all advanced breast cancer patients and generate major morbidity. The high ... [more ▼]

The skeleton is the privileged target of metastatic human breast cancer cells. Bone metastases are indeed found in virtually all advanced breast cancer patients and generate major morbidity. The high osteotropism of breast cancer cells suggests that they exhibit a selective affinity for mineralized tissues. The observation that mammary malignant cells are able to induce hydroxyapatite crystals deposition within the primary tumour suggests that they can generate a microenvironment that favors the crystallization of calcium and phosphate ions into the bone specific hydroxyapatite. Osteonectin (OSN), osteopontin (OPN) and bone sialoprotein (BSP), 3 bone matrix proteins involved in bone matrix mineralization, are expressed in human breast cancers. BSP, an RGD (Arg-Gly-Asp) containing phosphoprotein, initiates hydroxyapatite deposition and mediates attachment of osteoclast to the same crystals prior to their resorption. Detection of BSP at both the protein and the mRNA levels in human breast cancer and in human breast cancer cell lines (MCF-7, T47-D and MDA-MB 231) indicates that mammary malignant cells synthesize directly BSP rather than uptaking it from the serum. Interestingly, the level of BSP expression correlates with the development of bone metastases and with poor survival. These data suggest that the ectopic expression of bone matrix proteins could be involved in conferring osteotropic properties to circulating metastatic breast cancer cells. These observations open new alleys of investigation for the identification of the molecular mechanisms responsible for the genesis of bone metastases. [less ▲]

Expression of Bone Sialoprotein in Primary Human Breast Cancer Is Associated with Poor Survival

in International Journal of Cancer = Journal International du Cancer (1996), 69(4), 350-3

We have recently demonstrated that bone sialoprotein (BSP), a bone-matrix protein involved in hydroxyapatite crystal formation, is ectopically expressed in human breast cancers. We explored a possible ... [more ▼]

We have recently demonstrated that bone sialoprotein (BSP), a bone-matrix protein involved in hydroxyapatite crystal formation, is ectopically expressed in human breast cancers. We explored a possible association between expression of BSP in primary breast cancer and patients' survival. We analyzed BSP expression in 454 breast-cancer patients by immunohistochemistry on archival paraffin-embedded material using an anti-BSP polyclonal antibody. BSP expression was correlated to survival, tumor size, axillary lymph-node status and first site of distant metastasis. Of the breast cancers analyzed, 89% expressed detectable amounts of BSP. We found a statistical association between expression of BSP and poor prognosis as indicated by survival curves analyzed using the log rank and the Gehan methods. BSP expression was significantly higher in breast-cancer patients with axillary lymph-node involvement. Interestingly, survival of patients with positive lymph nodes but BSP-negative tumors was significantly higher than that of patients with no lymph-node involvement but BSP-positive cancers. The frequency of bone metastases was higher in the group of patients with BSP-positive tumors (22%) than in the group with BSP-negative cancers (7%). There was a significant increase in the incidence of lung metastases in patients whose tumors were negative for BSP. Our data show that bone sialoprotein expression in breast cancer is associated with poor prognosis. BSP detection also appears to be a valuable marker with which to identify, among the lymph-node-negative patients, those who have high risk of disease progression. [less ▲]

Bone Sialoprotein Expression in Primary Human Breast Cancer Is Associated with Bone Metastases Development

in Journal of Bone and Mineral Research (1996), 11(5), 665-70

Breast cancer metastasizes to bone more frequently than to any other organ, and over 80% of advanced breast cancer patients develop bone metastases. Our recent demonstration that human breast cancer cells ... [more ▼]

Breast cancer metastasizes to bone more frequently than to any other organ, and over 80% of advanced breast cancer patients develop bone metastases. Our recent demonstration that human breast cancer cells express bone sialoprotein (BSP), a bone matrix protein, provides a possible clue for the selective affinity of breast cancer cells for bone. We tested the hypothesis that detection of BSP in primary human breast cancer could be a potential indicator of the ability of breast cancer cells to metastasize to bone. BSP expression was evaluated in the primary breast cancers of 39 patients using immunoperoxidase and two specific anti-BSP antibodies. None of these patients presented clinically or scintigraphically detectable bone metastases at the time of surgery. In the course of their disease, 22 patients developed clinically diagnosed bone metastases. Expression of BSP in breast cancer cells from patients who developed bone metastases was significantly higher (p = 0.008, according to the Mann-Whitney test) than in patients with no bone involvement. No association was found between BSP expression in the primary breast lesions and axillary lymph node metastases. BSP expression was significantly increased in infiltrating ductal carcinoma compared with infiltrating lobular carcinoma (p = 0.0023). No correlation was found between immunoreactivity to BSP antibodies and estrogen receptor (ER) status, progesterone receptor (PR) status, or age. Our data suggest that BSP could help to identity which women will develop bone metastases and provide new bases for the understanding of the molecular mechanism(s) responsible for breast cancer cells osteotropism. [less ▲]

Increased Expression of Osteonectin and Osteopontin, Two Bone Matrix Proteins, in Human Breast Cancer

in American Journal of Pathology (1995), 146(1), 95-100

Microcalcifications are a common phenomenon associated with breast cancer and are often the only mammographic sign of a malignant breast disease. Although microcalcifications are not restricted to breast ... [more ▼]

Microcalcifications are a common phenomenon associated with breast cancer and are often the only mammographic sign of a malignant breast disease. Although microcalcifications are not restricted to breast cancer and can be also associated with benign lesions, it is noteworthy that they are composed exclusively of hydroxyapatite in breast carcinoma. Hydroxyapatite is the bone-associated phosphocalcic crystal the deposition of which in bone tissue requires the coordinated expression of several molecules such as osteonectin (OSN) and osteopontin (OPN), synthesized by cells of the osteoblastic lineage. In this study, we evaluated the expression of these two bone matrix proteins, using an immunoperoxidase technique and specific antibodies, in 79 breast lesions including 28 benign and 51 cancerous specimens. We found that normal mammary tissue associated with the lesions examined expressed generally undetectable or lightly detectable (0 or 1+) amounts of OSN and OPN (92 and 81%, respectively). Benign breast lesions, including fibroadenoma and fibrocystic dysplasia, were generally weakly stained (0 or 1+) with both anti-OSN and anti-OPN antibodies (96.4 and 60.7%, respectively). Interestingly, the majority of both in situ and invasive breast carcinoma lesions showed a strong expression (2+ or 3+) for OSN or OPN (74.5 and 84.3%, respectively). High expression of these two bone matrix proteins was associated with frequent microcalcification deposition in the lesion. This study is the first extensive study of OSN and OPN expression in mammary cancers. Our data suggest that OSN and OPN could play a role in the formation of ectopic microcalcifications often associated with breast cancer. It is also tempting to speculate that the expression of these two glycoproteins by breast cancer cells play a role in the preferred bone homing of breast metastases. [less ▲]

La protéine P53, protectrice de l'intégrité du génome: rôle dans la genèse des cancers

in Revue Médicale de Liège (1994), 49(5), 274-84

L'homéostasie des tissus de l'organisme est le résultat d'un équilibre dynamique stable entre des facteurs de régulation positifs et négatifs. Ceux-ci contrôlent la prolifération des cellules et ... [more ▼]

L'homéostasie des tissus de l'organisme est le résultat d'un équilibre dynamique stable entre des facteurs de régulation positifs et négatifs. Ceux-ci contrôlent la prolifération des cellules et déterminent leur appartenance tissulaire. Des données récentes indiquent que l'apparition des cancers résulte du déséquilibre de cet état dynamique soit part l'activation de facteurs positifs désignés sous le terme d'oncogènes, soit par l'inactivation de facteurs négatifs qui sont regroupés dans la famille des gènes suppresseurs de tumeurs. Le gène codant pour la protéine p53 est un membre particulièrement important de cette dernière famille. En effet, son inactivation, par mutation et/ou délétion, est l'une des altérations génétiques la plus fréquemment détectée dans les cancers. La fonction principale attribuée à la protéine p53 consiste à préserver le génome des altérations susceptibles d'entraîner, entre autres, la cellule dans un processus de transformation maligne. C'est en permettant la réparation des altérations du DNA survenues lors de sa réplication avant la mitose ou provoquées par des agents extérieurs, que la protéine p53 semble exercer ses fonctions. Des altérations du gène p53 entraînant des perturbations de la fonction de la protéine p53 ont été identifiées au niveau de la plupart des lésions tumorales malignes. A ce titre, cette protéine semble jouer un rôle déterminant au niveau de la genèse des cancers. Aussi le gène p53 fait-il l'objet de recherches intensives qui devraient déboucher sur la mise au point de nouveaux moyens de détection et d'évaluation pronostique des cancers. D'autre part, des expériences visant à restaurer la fonction de la protéine p53 au niveau des cellules cancéreuses ouvrent de nouvelles et séduisantes perspectives thérapeutiques. [less ▲]