Published in Cancer Detection and Prevention 1997; 21(5):441-451.

Heat Shock Proteins and Cell Proliferation in Human Breast Cancer Biopsy Samples

Laura M Vargas-Roig, MDa, Mariel A Fanelli, MBa, Luis A Lopez, PhDb, Francisco E Gago, MDc, Olga Tello, MDc, Juan C Aznar, MDc, and Daniel R Ciocca, MD, PhDa

aLaboratory of Reproduction and Lactation, Regional Center for Scientific and Technological Research, Mendoza, Argentina; bInstitute of Histology and Embriology, Faculty of Medicine, National University of Cuyo, Mendoza, Argentina; cProvincial Hospitals of Mendoza, Mendoza, Argentina

Address all correspondence and reprint requests to: Daniel R Ciocca, MD, PhD, Laboratory of Reproduction and Lactation (LARLAC), Casilla de Correo 855, 5500 Mendoza, Argentina.

ABSTRACT: Human breast cancers may overexpress certain heat shock protein (hsp) family members, proteins which are involved with cell proliferation and differentiation as well as with disease prognosis and drug resistance. Here, we have studied the relationship between the expression of two hsps (hsp27 and hsp70) and the proliferative activity of tumor cells in 40 biopsies from breast cancer patients. Twenty of these tumors were selected for a detailed colocalization study. Immunocytochemistry was done using specific antibodies against hsp27 and hsp70. Cell proliferation was studied analyzing the expression of proliferating cell nuclear antigen (PCNA) (late G1, S, and G2 phases of the cell cycle) and the number of silver-staining nucleolar organizer regions (AgNORs) (Gl phase). The colocalization study revealed a statistically significant inverse correlation between hsp27 expression and cell proliferation in 16/19 (84%) of the cases evaluated by PCNA immunostaining, and in 11/16 (69%) of the cases evaluated by AgNORs. In contrast, a statistically significant positive correlation between hsp70 expression and elevated cell proliferation was seen in almost 85% of the cases evaluated by PCNA staining, and in almost 50% of the cases evaluated by AgNORs. Moreover, in 22% (9/40) of the breast cancer samples examined, hsp70 was 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 noted in lung carcinoma samples (N = 20) or in normal cells displaying elevated mitotic activity. These studies thus demonstrate that in a significant 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 results 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 studies will be necessary to elucidate these possible cause-and-effect relationships.

KEY WORDS: breast cancer, cell proliferation, heat shock proteins.