HEAT-SHOCK PROTEINS AND CELL-PROLIFERATION IN HUMAN BREAST-CANCER BIOPSY SAMPLES

Human breast cancers may overexpress certain heat shock protein (hsp) family members, proteins which are involved with cell proliferation an d differentiation as well as with disease prognosis and drug resistanc e. Here, we have studied the relationship between the expression of tw o hsps (hsp27 and hsp70) and the proliferative activity of tumor cells in 40 biopsies from breast cancer patients. Twenty of these tumors we re selected for a detailed colocalization study. Immunocytochemistry w as done using specific antibodies against hsp27 and hsp70. Cell prolif eration was studied analyzing the expression of proliferating cell nuc lear antigen (PCNA) (late G1, S, and G2 phases of the cell cycle) and the number of silver-staining nucleolar organizer regions (AgNORs) (G1 phase). The colocalization study revealed a statistically significant inverse correlation between hsp27 expression and cell proliferation i n 16/19 (84%) of the cases evaluated by PCNA immunostaining, and in 11 /16 (69%) of the cases evaluated by AgNORs. In contrast, a statistical ly significant positive correlation between hsp70 expression and eleva ted cell proliferation was seen in almost 85% of the cases evaluated b y PCNA staining, and in almost 50% of the cases evaluated by AgNORs. M oreover, in 22% (9/40) of the breast cancer samples examined, hsp70 wa s clearly associated with the mitotic spindle. A Western blot analysis revealed that hsp70 was coprecipitated with taxol-polymerized tubulin . The association of hsp70 with the mitotic spindle was not clearly no ted in lung carcinoma samples (N = 20) or in normal cells displaying e levated mitotic activity. These studies thus demonstrate that in a sig nificant percentage of clinical breast cancers hsp27 overexpression is inversely correlated with cell proliferation, while hsp70 is clearly associated with the mitotic spindle and cell proliferation. These resu lts add evidence to the concept that in human breast cancers hsp27 may be involved in cell growth arrest and increased differentiation while , in contrast, hsp70 may be involved in cell proliferation; further st udies will be necessary to elucidate these possible cause-and-effect r elationships.