Specific increase of human kallikrein 4 mRNA and protein levels in breast cancer stromal cells

https://doi.org/10.1016/j.bbrc.2008.07.138Get rights and content

Abstract

The kallikrein family (KLK) has been implicated in cancer and may be useful as tumor markers. Here, we compared the 15 KLK genes’ expression in malignant and normal breast tissues using real-time quantitative PCR. Most KLKs were expressed at lower levels in breast cancer compared to normal breast tissue. The only exception was the eightfold increase level of KLK4 in breast cancer tissues (P = 0.008). KLK4 level was strongly associated with tumor grade (P = 0.0015). Interestingly, based on laser cell microdissection analysis and immunochemistry, the up-regulation of kallikrein 4 occurred in the surrounding stromal cells. Our findings suggest that KLK4 may be associated with the development and progression of breast cancer and suggest its potential use in breast cancer monitoring.

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Materials and methods

Patients and sample collection. Primary breast carcinomas tissues were collected surgically from 37 patients at the Val d’Aurelle Cancer Center, Montpellier, France. Clinicopathological data were described in Table 1. The control group was from 14 healthy women who underwent surgery for mammary reduction. Tumor and normal tissues were immediately frozen in liquid nitrogen after surgery and stored at −80 °C. Sera from five cancer patients and five healthy volunteers were stored at −80 °C. Informed

KLK expression in normal and cancerous breast tissues

We analyzed the expression of the 15 KLK genes in 51 tissues from 14 normal and 37 breast cancer patients. In our conditions, the threshold cycle values for KLK5, 13 and 15 mRNA were undetectable. We then compared mRNA expression levels of the other 12 KLK genes using relative quantification by comparative Ct (Table 2). When mRNA expression in tumor tissues was examined, nine KLK mRNAs showed statistically significant lower expression levels in tumors compared to normal breast tissues. There

Discussion

In contrast to the multiple studies examining a small set of KLKs, we quantitatively analyzed the expression pattern of 15 serine proteases in benign and malignant human breast cancer tissues by real-time PCR, in order to evaluate their usefulness as diagnostic tools. We observed a major down-regulation of most KLK genes in breast tumors compared to normal tissues, while KLK4 was shown, for the first time, to be strongly up-regulated in breast cancer tissues. We observed concordant increase of

Acknowledgements

The authors are grateful to Pr H Rochefort for critical reading of the manuscript. The authors are also grateful to Pr P. Rouanet (CRLC Val d’Aurelle, Department of Surgery, Montpellier, France) and Dr F. Bibeau (CRLC Val d’Aurelle, Department of Pathology, Montpellier, France), which provided the breast tissue samples and sera used for this study.

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      In one study, KLK5, KLK6, KLK10 and KLK12 were reported to be down-regulated in breast cancer tissues [19]. In another study, mRNA levels of nine out of 12 detectable KLK genes namely, KLK1, KLK2, KLK6, KLK7, KLK9, KLK10, KLK11, KLK12 and KLK14, were found to be significantly down-regulated in malignant breast tissues [20]. Parallel down-regulation of KLK5 and KLK7 mRNA levels in breast cancers has also been reported [21,22].

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      Similarly, in almost 100% of gastric cancer datasets, KLK6 and KLK10 were significantly increased, whereas KLK11 was reduced as previously reported [93–95]. KLK4 seemed to be the only KLK clearly upregulated in the breast cancer datasets as already demonstrated at both mRNA and protein levels [96], whereas KLK5-8 and KLK10 were down-regulated in the majority of datasets available. For further details of KLK expression in other malignant tissues please refer to Table 1.

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