Abstract 474: Cx43 mutant mice show delayed formation of palpable mammary gland tumors but are more susceptible to lung lesions

Abstract Gap junctional intercellular communication is essential for the regulation of cell proliferation, differentiation and tissues homeostasis. Gap junctions are composed of channels, formed by proteins called connexins (Cx). It has been proposed that connexins can act as tumor suppressors in a wide variety of tumor types. However, their role in breast cancer remains poorly understood. We previously showed that Gja1Jrt/+ (G60S) mice, harboring a G60S dominant-negative Cx43 mutation, have reduced levels of Cx43 in the mammary gland. This study aimed to determine if low levels of Cx43 render mice more susceptible to breast cancer and/or result in more aggressive tumors. G60S mice were crossbred with ErbB2 mice (or FVB control mice), that spontaneously develop mammary gland tumors. Similar to G60S mice, G60S-ErbB2 mice showed decreased Cx43 protein levels and fewer gap junction plaques, compared to control ErbB2 mice (WT-ErbB2). Mice were exposed to 5 weekly doses of 7,12-dimethylbenz(a)anthracene (DMBA) starting at 7 weeks old and sacrificed when tumors reached approximately 1 cm3 or when mice showed signs of illness. Tumor onset and progression were evaluated by palpation every week. Surprisingly, while tumors were detected in 50% of WT-ErbB2 and WT-FVB mice by 32 and 36 weeks of age, respectively, only 14% of G60S-ErbB2 and 44% of G60S-FVB mice had palpable tumors by week 42, suggesting that low levels of Cx43 delay the onset of tumors. Tumor growth rates were similar in all groups, but while tumors from WT-ErbB2 and WT-FVB mice reached the threshold of 1 cm3, most Cx43 mutant mice started to show labored breathings around 40 weeks, independent of the presence of palpable tumors. Lung examination revealed the presence of lesions in 80% of WT-FVB and 69% WT-ErbB2 mice, compared to 100% for G60S-ErbB2 and G60S-FVB mice. Moreover, Cx43 mutant mice had an average of 20 visible lung lesions compared to only 6 for WT groups. Preliminary results showed that at least some of the mutant mice present signs of mammary gland hyperplasia, suggesting that low levels of Cx43 could potentially result in more aggressive hyperplasic breast cells that metastasize to the lungs. Future experiments will determine whether lesions are of lung or breast origin. Together, our results suggest that low levels of Cx43 delayed the presence of palpable tumors in mammary gland, but increased the number of lung lesions. Supported by the CBCRA, CIHR and FRSQ. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 474.

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