Molecular mechanisms in tumor progression and breast cancer metastasis

Principal Investigator: Professor Elvira Mustać

Department: Department of Pathology, Faculty of Medicine

Institution: University of Rijeka, Croatia


Key words: breast cancer, progression, metastasis, nEGFR, PTTG1, AR Kalpain 1

Breast cancer is a clinically heterogeneous disease, often unpredictable course despite the known prognostic factors. Histologically similar tumors may have a different prognosis and response to therapy due to molecular differences between histologically similar tumors. It is known that androgens play an important role in the physiology of the breast, while signaling the androgen receptor (AR) is recognized as an important factor in breast cancer carcinogenesis. Studies have shown that AR is, somewhat paradoxically, the most expressed nuclear hormone receptor in breast cancer. And despite this fact, the AR is not evaluated routinely because there was no effect on the response to the currently used therapies, in contrast to the ER and PR. The success of ER / PR and HER2-targeted therapy is redirected towards the AR for those breast cancers that do not express ER / PR and / or HER2-called triple negative cancers. It seems that in these cancers is particularly important calpain in a manner that elevated expression of calpain 2 is associated with shorter survival. Calpain 1 showed the effect on disease free survival and is associated with poor prognosis in HER2 positive tumors treated with adjuvant chemotherapy. It was hypothesized that the survival of different tumor cells exposed to therapeutic agents depends in part on the activation of signaling pathways and protein-dependent calpain. Thus, increased expression of calpain leads to the proliferation and development of HER2 positive tumors resistant to trastuzumab, while the inhibition is associated with a reduced proliferation and increased sensitivity to a specific therapy. Identification of new biomarkers can help in early diagnosis and potential target effective therapeutic strategies. One of the new indicators is the pituitary tumor transforming gene 1 (PTTG1), which was detected in several tumor histologically unrelated origin, and its expression level is associated with aggressiveness of the primary tumour. It is known that overexpression PTTG1 is leading to aneuploidy, causes in vitro transformation and tumor formation in vivo, regulates the secretion of basic fibroblast growth factor and stimulates angiogenesis. Since in ductal carcinoma of breast PTTG1 showed the opposite path of activation than signaling pathways analogues such as securin, observed activity PTTG1 could be of great clinical importance because it effectively shows the capacity for tumor proliferation and quite possibly at the same time present association with p53 mutation oncogene that indicates a worse prognosis, shorter recurrence interval and disease progression.