Molecular chaperones in mammary cancer growth and breast tumor therapy

Abstract

Heat shock protein (HSP) levels are elevated in breast cancer and are molecular targets for novel therapies. HSPs were first observed as proteins induced in massive amounts in normal cells exposed to stresses that lead to protein denaturation. Their expanded expression in mammary carcinoma appears to be largely due to the proliferation of malfolded mutant proteins and overexpressed oncoproteins that trigger transcription of HSP genes. HSPs play major roles in malignant transformation and progression mediated through their intrinsic molecular chaperone properties. These permit the emergence of new malignant traits through the facilitated accumulation of altered oncoproteins. The elevation of HSP concentrations in mammary carcinoma is at least partially dependent on heat shock transcription factor 1 (HSF1), a protein that responds to unfolded proteins and leads to HSP transcription. HSF1 activation has additional downstream activities, crucial for emergence of the breast cancer phenotype and these include activated cell signaling, HSP-mediated ability to evade apoptosis and senescence and an HSF1-dependent bias in transcriptional activity towards a metastatic phenotype. The HSPs are currently being targeted in breast cancer therapy and effective drugs for Hsp90 have been synthesized and evaluated in clinical trial. Mammary carcinoma cells also contain abundant quantities of HSP–tumor antigen complexes and these complexes are being used to develop effective tumor vaccine approaches that provide personalized therapy for each individual's cancer.

Figure (1). Role of HSPs in evolution of breast carcinogenesis

We show a normal population of mammary cells containing range of HSP concentrations. In a small percentage of the population a tumor initiating mutation occurs, leading to the expression of mutant oncoproteins. Higher levels of HSPs will be required to chaperone the aberrant conformation of the oncoprotein, favoring outgrowth of cells with elevated HSPs. Tumorigenisis often involves multiple mutational events and these will select for cells with progressively higher HSP levels to deal with the protein stress. Elevated levels of HSPs thus permit the build up of genetic diversity in the mammary tumor cell population, helping to drive evolution of the tumor phenotype and permit response to adverse conditions and tumor therapy. Elevated levels of HSPs proect the emerging tumor cells from apoptotic death and senescene, drive proliferation by chaperoning oncogenes. In addition, elevated levels of HSPs and HSF1 will promote tumor progression by permitting cell survival in the circulation and repressing regulatory genes that may inhibit invasion and metastasis

Figure (2). Induction of HSP expression in mammary carcinoma

Elevated expression of mutated / overexpressed oncoproteins activates HSF1 and leads to elevated HSP expression in mammary carcinomata. HSP expression may also be activated through breast cancer signaling pathways altered in cancer, including the HER2/ PI-3-kinase pathway. The Hsp70 gene is repressed by p53 family proteins either through HSF1 or by direct effects on the HSP70 promoter and these effects are reversed in cells in which p53 proteins are inactivated.

Figure (3)

Roles for HSF1, Hsp27 and Hsp90 in mammary cell carcinogenesis and breast cancer progression.

Figure(4). Molecular chaperone vaccines

Hsp70 and hsp90 bind to intracellular proteins in mammary carcinoma cells and transport them to the proteasome, where they are hydrolyzed to smaller peptides. Intracellular Hsp70 and Hsp90 can then bind and chaperone the processed peptides. The chaperones complexed with processed and unprocessed polypeptide antigens can then be harvested from cells after lysis and used to prepare molecular chaperone anti-breast cancer vaccines.