Breast cancer is the most commonly diagnosed cancer in women. Despite recent advances in screening and early detection, breast cancer continues to result in a high incidence of morbidity and mortality. In its late stage the majority of patients exhibit signs of destructive skeletal metastasis. This complication is promoted by the production of growth factors by tumor cells which can induce tumor cell proliferation via their interaction with their respective receptors to initiate the vicious cycle of bone resorption. Inhibition of growth factors signaling through their receptors can therefore serve as a useful therapeutic approach to block bone metastasis. / The biological characteristics of cancer cells along with the targeting properties of immune system offer a novel approach in the treatment of breast cancer. Directed against HER-2/nue oncogene, the recombinant humanized monoclonal antibody, Trastuzumab (Herceptin), has shown significant clinical benefits for the treatment of HER-2 positive metastatic breast cancer. / In the present study, the effects of Herceptin and its molecular mechanism of action in abrogating the development and progression of osteolytic bone metastasis is investigated in an experimental mouse model of skeletal metastasis using human breast cancer cells BT-474 which are known to express high levels of HER-2. Treatment of BT-474 cells with Herceptin caused a dose dependent decrease in cell proliferation. In in vivo studies BT-474 cells were injected by into the left ventricle of female BALB/c nu/nu mice. Intraperitoneal infusion of Herceptin from the day of tumor cell inoculation or at the time of radiologically detectable skeletal metastasis either slowed the development or prevented the progression of skeletal metastasis as compared to control groups of animals receiving non-specific IgG. Bone histological analysis of long bones showed the ability of Herceptin to reduce the ratio of tumor volume to bone volume as well as mitotic index when Herceptin treatment was initiated from the day of tumor cell inoculation. Immunohistochemical analysis of long bones showed a significantly lower level of activated (phosphorylated) MAPK in bones of Herceptin treated animals. These studies demonstrate the ability of Herceptin to inhibit the development and abrogate the progression of skeletal metastasis associated with breast cancer by blocking the HER-2 mediated signaling pathways.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Thesis (M.S.)--University of South Florida, 2006. / Title from PDF of title page. Document formatted into pages; contains 58 pages. Includes bibliographical references.

Thesis (Ph. D.)--University of New South Wales, 2007. / Title from caption (viewed on May 7, 2008).

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 5 uppsatser.

Thesis (M.S.)--West Virginia University, 2006. / Title from document title page. Document formatted into pages; contains ix, 98 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 92-98).

Abstract The invasion of a tumour through tissue limiting basement membranes is the critical step in malignant growth. Gelatinases (MMP-2 and MMP-9) are endopeptidases capable of degrading extracellular and pericellular matrix proteins such as collagen IV, the major component of basement membranes. An over-expression of these gelatinases is generally found in malignant tumours and is linked to impaired prognosis in many cancer types. Tissue inhibitors of metalloproteinases (TIMPs), endogenous regulators of the MMP activity, have recently been introduced as multifunctional proteins, which have paradoxical roles in tumour growth. Little data exists on the clinical significance of the gelatinases and TIMPs in gynaecological cancers. In this study the clinical significance of the gelatinases was studied in endometrial and uterine cervical cancers by using immunohistochemical staining with specific antibodies. In epithelial ovarian cancer (EOC) these enzymes and their TIMPs were studied in the preoperative serum samples using ELISA assay. Additionally, sequential serum measurements were performed during chemotherapy to evaluate them as treatment response indicators. In endometrial cancer, MMP-9 positivity correlated to a poor histological differentiation and an advanced clinical stage. High MMP-2 expression correlated to a poor differentiation, and unfavourable survival in stage I cancers, with mortality rates of 5% and 19% in patients with MMP-2 negative versus intensively MMP-2 positive tumours, respectively. In cervical cancers high MMP-2 expression correlated to an increased mortality risk. High MMP-9 expression was connected to a good differentiation of a tumour. In EOC, a high circulating TIMP-1 value correlated to all the examined aggressive features of EOC, including poor survival. The serum measurements of TIMP-1 were uninformative about response evaluation during chemotherapy but paradoxically, an increase in gelatinases and TIMP-2 seemed to reflect a good response to treatment. In conclusion, the data from this study show that high MMP-2 expression in tumour tissue could be prognostic in endometrial and cervical cancer, and preoperative circulating TIMP-1 could serve as an additional prognostic marker in EOC. Studies with larger patient cohorts would be necessary to further explore the value of these enzymes in clinical practice in gynaecological cancers.

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