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 primary tumors (including mammary tumors) have little or no gap junctional intercellular communication (GJIC). 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. In the Laird laboratory we focus on Cx43 and Cx26 as they are the only two connexins expressed in 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. Mammary gland specific deletions of connexins in mouse models are also being used to investigate the tumor protective properties of connexins.
Malignant melanoma is one of the most deadly cancers accounting for ~79% of all skin cancer-related deaths. Analysis of a limited sample archive reported in the Human Protein Atlas revealed that Panx1 is up-regulated in ~70% of all human melanoma tumors samples. High levels of Panx1 were also found in lung, colorectal and non-melanoma skin cancer samples suggesting that Panx1 may be important in tumor onset and/or progression. We have found that Panx1 is expressed at low levels in skin melanocytes and is highly upregulated in malignant melanoma cells. Upon Panx1-knockdown, melanoma cells resemble normal melanocytes in cell morphology and melanin production, exhibiting reduced migration and growth. In vivo, Panx1-depleted cells formed smaller melanoma tumors in the chick chorioallantoic membrane and had significantly reduced metastasis to the liver of the avian embryos. Therefore, we propose that Panx1 is significantly up-regulated as melanocytes transform into melanomas and, moreover, a targeted knockdown of Panx1 may reduce the tumorigenic properties of melanomas. Thus, in this research project, we are continuing to examine the role of pannexins in melanoma disease progression and assessing whether it may be a possible therapeutic target.
M.K.G. Stewart, I. Plante, S. Penuela and D.W. Laird (2016) “Loss of Panx1 impairs mammary gland development at lactation: implications for breast tumorigenesis” PLoS One 11(4):e0154162. doi: 10.1371
M.K.G. Stewart, J.F. Bechberger, I. Welch, C.C. Naus and D. W. Laird (2015) “Cx26 knockdown predisposes the mammary gland to primary mammary tumors in a DMBA-induced mouse model of breast cancer” Oncotarget 6: 37185-37199.
R. Nahta, F. Al-Mulla, R. Al-Temaimi, A. Amedie, R. Andrade-Vieira, S. Bay, D. Brown, G. Calaf, R.C. Castellino, K.A. Chone-Solal, N. Cruickshanks, P. Dent, R. Di Fiore, St. Forte, G.S. Goldberg, R. A. Hamid, H. Krishnan, D.W. Laird, A. Lasfar, P. Marignani, L. Memeo, C. Mondello, C.C. Naus, R. Ponce-Cusi, J. Raju, D. Roy, R. Roy, E. Ryan, H.K. Salem, I. Scovassi, N. Singh, M. Vaccari, R. Vento, J. Vondracek, M. Wade, J. Woodrick and W. H. Bisson (2015) “Mechanisms by which cancer cells evade growth suppression and the potential molecular effects of selected environmental chemicals” Carcinogenesis 36: S2-S18.
M.J. Ableser, S. Penuela, Q. Shao, J. Lee and D.W. Laird (2014) “Connexin43 reduces melanoma growth within a keratinocyte microenvironment and during tumorigenesis in vivo” Journal of Biological Chemistry 289: 1592-1603.
A. Boyd-Tressler, S. Penuela, D.W. Laird and G.R. Dubyak (2014) “Chemotherapeutic drugs induce ATP release via caspase-gated pannexin-1 channels and a caspase/pannexin-1 independent mechanism” Journal of Biological Chemistry 289: 27246-27263.
Stewart, X.-Q, Gong, K.J. Barr, D. Bai, G.I. Fishman and D.W. Laird (2013) “Mammary gland defects as revealed by genetically-modified mice harboring an oculodentodigital dysplasia-linked Cx43 mutant” Biochemical Journal 449: 401-413.
I. Plante, M.K.G. Stewart and D.W. Laird (2011) “Evaluation of mammary gland development and function in mouse models” Journal of Visualized Experiments 53: pii:2828.
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.
E. McLachlan, Q. Shao and D.W. Laird (2007) “Connexins and gap junctions in mammary development and breast cancer progression” Journal of Membrane Biology 218: 107-121
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