Abstract
BackgroundAbnormal levels of Heat Shock Proteins (HSPs) have been observed in many human neoplasms including breast cancer and it has been demonstrated that they have both prognostic and therapeutic implications. In this study, we evaluated immunohistochemical expression of HSPs in normal and neoplastic canine mammary glands and confronted these results with overall survival (OS), in order to understand the role of HSPs in carcinogenesis and to establish their potential prognostic and/or therapeutic value.MethodsImmunohistochemical expression of Hsp27, Hsp72, Hsp73 and Hsp90 was evaluated in 3 normal canine mammary glands and 30 malignant mammary tumours (10 in situ carcinomas, 10 invasive carcinomas limited to local structures without identifiable invasion of blood or lymphatic vessels, 10 carcinomas with invasion of blood or lymphatic vessels and/or metastases to regional lymph nodes). A semi-quantitative method was used for the analysis of the results.ResultsWidespread constitutive expression of Hsp73 and Hsp90 was detected in normal tissue, Hsp72 appeared to be focally distributed and Hsp27 showed a negative to rare weak immunostaining. In mammary tumours, a significant increase in Hsp27 (P < 0.01), Hsp72 (P < 0.05) and Hsp90 (P < 0.01) expression was observed as well as a significant reduction in Hsp73 (P < 0.01) immunoreactivity compared to normal mammary gland tissue. Hsp27 demonstrated a strong positivity in infiltrating tumour cells and metaplastic squamous elements of invasive groups. High Hsp27 expression also appeared to be significantly correlated to a shorter OS (P = 0.00087). Intense immunolabelling of Hsp72 and Hsp73 was frequently detected in infiltrative or inflammatory tumour areas. Hsp90 expression was high in all tumours and, like Hsp73, it also showed an intense positivity in lymphatic emboli.ConclusionThese results suggest that Hsp27, Hsp72 and Hsp90 are involved in canine mammary gland carcinogenesis. In addition, Hsp27 appears to be implicated in tumour invasiveness and its high immunodetection in invasive tumours is indicative of a poorer clinical outcome.
Highlights
Abnormal levels of Heat Shock Proteins (HSPs) have been observed in many human neoplasms including breast cancer and it has been demonstrated that they have both prognostic and therapeutic implications
HSP expression in normal mammary gland Hsp27 immunoreactivity was practically absent in normal canine mammary gland (Figure 1a)
Hsp90 is essential for the stability and function of steroid hormone receptors [36], as well as the membrane receptor tyrosine kinase ErbB2 [37], whose enhanced expression correlates with malignancy of breast cancer progression [25] and which might play an important role in carcinogenesis of canine mammary gland [38,39,40,41]
Summary
Abnormal levels of Heat Shock Proteins (HSPs) have been observed in many human neoplasms including breast cancer and it has been demonstrated that they have both prognostic and therapeutic implications. Heat Shock Proteins (HSPs) or Stress Proteins are one of the most evolutionarily conserved classes of molecule and play a fundamental role in the maintenance of cellular homeostasis. Under physiological conditions, they act as "molecular chaperones", by assisting protein folding, transport and degradation; during stress, on the other hand, they prevent aggregation and promote refolding of damaged proteins. Tumour cells appear to be dependent on increased levels of these proteins, since elevated expression of different HSPs has been observed in several human neoplastic conditions [6]. HSPs appear to be promising therapeutic targets for several kinds of tumours, including breast cancer [21,22,23,24,25,26]
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