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Research Articles: Targets

Telomerase inhibition enhances the response to anticancer drug treatment in human breast cancer cells

¹ Department of Anatomy and Cell Biology and ² Bloomfield Centre for Research in Aging, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada; and ³ Telomeres and Cancer Laboratory, UMR7147 CNRS-IC-UPMC, Institut Curie, Paris, France

Requests for reprints: Chantal Autexier, Bloomfield Centre for Research in Aging, Lady Davis Institute, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote Ste Catherine, Montreal, Quebec, Canada H3T 1E2. Phone: 514-340-8260; Fax: 514-340-8295. E-mail: chantal.autexier{at}mcgill.ca

Breast cancer is the most common malignancy among women. Current therapies for breast tumors are based on the use of chemotherapeutic drugs that are quite toxic for the patients and often result in resistance. Telomerase is up-regulated in 95% of breast carcinomas but not in adjacent normal tissues. Therefore, it represents a very promising target for anticancer therapies. Unfortunately, the antiproliferative effects of telomerase inhibition require extensive telomere shortening before they are fully present. Combining telomerase inhibition with common chemotherapeutic drugs can be used to reduce this lag phase and induce tumor cell death more effectively. Few studies have analyzed the effects of telomerase inhibition in combination with anticancer drugs in breast cancer cells. In this study, we inhibited telomerase activity in two breast cancer cell lines using a dominant-negative human telomerase reverse transcriptase and analyzed cell viability after treatment with different anticancer compounds. We found that dominant-negative human telomerase reverse transcriptase efficiently inhibits telomerase activity and causes telomere shortening over time. Moreover, cells in which telomerase was suppressed were more sensitive to anticancer agents independently of their mechanism of action and this sensitization was dependent on the presence of shorter telomeres. Altogether, our data show that blocking telomere length maintenance in combination with anticancer drugs can be used as an effective way to induce death of breast cancer cells. [Mol Cancer Ther 2006;5(7):1669–75]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: C. Autexier is a chercheur-boursier of the Fonds de la Recherche on Santé du Quebec.

M.A. Cerone was supported by U.S. Army Department of Defense Breast Cancer Research Program Award.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 1/20/06; revised 4/26/06; accepted 5/ 2/06.