Breast cancer is one of the most serious and prominent health conditions to face women today. Approximately one in nine Canadian women will develop breast cancer at some stage of their life. Patients with advanced breast cancer respond poorly to conventional treatments, presumably due to the presence of drug resistant tumors. It has been well established that many tumors (including mammary tumors) have little or no gap junctional intercellular communication (GJIC).
Cancer Growth Analysis
Up-regulation of gap junctions in a number of tumor cell lines results in growth suppression both in vitro and in vivo, suggesting that at least some members of the gap junction family called connexins (Cx), are tumor suppressors. Cx43 and Cx26 remain the only two connexins that have been conclusively identified to be resident connexins of the human breast epithelium.
It is our hypothesis that down-regulation of GJIC plays a role in breast cancer development, progression and metastasis. In this study we are examining the mechanism of how gap junctions are down-regulated in mammary tumor cells and investigating possible therapeutic implications of up-regulating gap junctions in human mammary tumor cells. Many of these studies are now being performed in vivo or in 3 dimensional models.
Mammary gland specific deletions of connexins in mouse models are also being used to investigate the tumor protective properties of connexins. Finally, research into the identification and characterization of molecules that specifically interact with connexins is ongoing.
These studies are supported by the Canadian Breast Cancer Research Alliance and involve direct collaborations with Dr. Christian Naus at the University of British Columbia and Dr. Moulay Alaoui-Jamali at the Lady Davis Institute in Montreal.
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I. Plante, M.K.G. Stewart, K. Barr, A.L. Allan and D.W. Laird (2011) “Cx43 suppresses mammary tumor metastasis to the lung in a Cx43 mutant mouse model of human disease” Oncogene 30:1681-1692.
C.C. Naus and D.W. Laird (2010) “Implications and challenges of connexin connections in cancer” Nature Reviews Cancer 10: 435-441.
S. Langlois, K.N. Cowan, Q. Shao, B.J. Cowan and D.W. Laird (2010) “The tumor suppressive function of connexin43 in keratinocytes is mediated in part via interaction with caveolin-1” Cancer Research 70: 4222-4232.
I. Plante, A. Wallis, Q. Shao and D.W.Laird (2010) “Milk secretion and ejection are impaired in the mammary gland of mice harboring a Cx43 mutant but molecular constituents of tight and adherens junctions remain intact” Biology of Reproduction 82: 837-847.
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E. McLachlan, Q. Shao, H. Wang, S. Langlois and D.W. Laird (2006) “Molecular mechanisms associated with the role of connexins as tumour suppressors in 3-dimensional mammary cell organoids” Cancer Research 66: 9886-9894.Article featured on BreastCancer.Net News
J. Kalra, Q. Shao, H. Qin, T. Thomas, M.A. Alaoui-Jamali and D.W. Laird (2006) “Cx26 inhibits breast MDA-MB-435 cell tumorigenic properties by a gap junctional intercellular communication-independent mechanism” Carcinogenesis27: 2528-2537. Article featured on BreastCancer.Net News
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