Cx26 knockout predisposes the mammary gland to primary mammary tumors in a DMBA-induced mouse model of breast cancer
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Michael K.G. Stewart1, John F. Bechberger2, Ian Welch4, Christian C. Naus2 and Dale W. Laird1,3
1 Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
2 Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada
3 Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada
4 Animal Care and Veterinary Services, University of Western Ontario, London, Ontario, Canada
Dale W. Laird, email:
Keywords: connexin26, mammary gland, breast cancer, DMBA
Received: May 22, 2015 Accepted: September 17, 2015 Published: October 02, 2015
Down-regulation of the gap junction protein connexin26 (Cx26) is an early event following breast cancer onset and has led to Cx26 being classically described as a tumor suppressor. Interestingly, mutations in theCx26 gene (GJB2) reduce or ablate Cx26 gap junction channel function and are the most common cause of genetic deafness. It is unknown if patients with loss-of-function GJB2 mutations have a greater susceptibility to breast tumorigenesis or aggressive breast cancer progression. To investigate these possibilities, 7, 12-dimethylbenz[α]anthracene (DMBA)-induced tumor development was evaluated in BLG-Cre; Cx26fl/fl mice expressing Cre under the β-Lactoglobulin promoter (Cre+) compared to Cx26fl/fl controlmice (Cre-) following pituitary isograft driven Cx26 knockout. A significantly increased number of DMBA-treated Cre+ mice developed primary mammary tumors, as well as developed multiple tumors, compared to Cre- mice. Primary tumors of Cre+ mice were of multiple histological subtypes and had similar palpable tumour onset and growth rate compared to tumors from Cre- mice. Lungs were evaluated for evidence of metastases revealing a similar percentage of lung metastases in Cre+ and Cre- mice. Together, our results suggest that loss of Cx26 predisposes the mammary gland to chemically induced mammary tumour formation which may have important implications to patients with GJB2 mutations.
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