Abstract
Considerable epidemiological evidence demonstrates a positive association between artificial light at night (LAN) levels and incidence rates of breast cancer, suggesting that exposure to LAN is a risk factor for breast cancer. There is a 30-50% higher risk of breast cancer in the highest LAN exposed countries compared to the lowest LAN countries, and studies showing higher incidence of breast cancer among shift workers exposed to more LAN have led the International Agency for Research on Cancer to classify shift work as a probable human carcinogen. Nevertheless, the means by which light can affect breast cancer is still unknown. In this study we examined established human breast cancer cell lines and patients’ primary breast cancer tissues for expression of genetic components of phosphodiesterase 6 (PDE6), a cGMP-specific PDE involved in transduction of the light signal, and previously thought to be selectively expressed in photoreceptors. By microarray analysis we find highly significant expression of mRNA for the PDE6B, PDE6C, and PDE6D genes in both the cell lines and patients’ tissues, minimal expression of PDE6A and PDE6G and no expression of PDE6H. Using antibody specific for PDE6β, we find expression of PDE6B protein in a wide range of patients’ tissues by immunohistochemistry, and in MCF-7 breast cancer cells by immunofluorescence and Western blot analysis. Considerable expression of key circadian genes, PERIOD 2, CLOCK, TIMELESS, CRYPTOCHROME 1, and CRYPTOCHROME 2 was also seen in all breast cancer cell lines and all patients’ breast cancer tissues. These studies indicate that genes for PDE6 and control of circadian rhythm are expressed in human breast cancer cells and tissues and may play a role in transducing the effects of light on breast cancer.
Highlights
Cyclic Nucleotide Phosphodiesterases (PDEs) are encoded by 21 different genes grouped into 11 gene families based on sequence similarity, mode of regulation, and specificity for cAMP or cGMP as substrate (Francis, et al 2011; Lerner and Epstein 2006)
Expression of phosphodiesterase 6 (PDE6) mRNA in breast cancer cell lines Expression of the mRNA for PDE6 genes was examined in the human breast adenocarcinoma estrogen receptornegative cell lines, MB-231 and MB-435, and in the estrogen receptor-positive cell lines, T47D and MCF-7, by microarray analysis
Some melanoma cell lines expressed Wnt5a and Frizzled-2, and in these cell lines Wnt5a stimulated PDE6 activity, suggesting that in melanoma, PDE6 may be activated either by light impinging on rhodopsin, which is expressed in these cells, or by Wnt5a acting through Frizzled-2 and transducin (Bazhin, et al 2010)
Summary
Cyclic Nucleotide Phosphodiesterases (PDEs) are encoded by 21 different genes grouped into 11 gene families based on sequence similarity, mode of regulation, and specificity for cAMP or cGMP as substrate (Francis, et al 2011; Lerner and Epstein 2006). The PDE6Dencoded δ subunit (PDE6δ) is not specific to PDE6 in that it binds to other enzymes and is expressed in other tissues (Zhang, et al 2004). The γ inhibitory subunit of PDE6 is expressed in other tissues such as lung and kidney cells (Guo and Ruoho 2008; Tate, et al 2002) and has been suggested to play a role in the activation of MAP kinase by epidermal growth factor signaling (Wan, et al 2003). In chick, both in rods and pineal glands, the catalytic activity of PDE6 appears to be comprised of homodimers of two PDE6B-encoded β subunits, with no evidence for the expression of PDE6A-encoded α subunits present in these chick tissues (Huang, et al 2004; Morin, et al 2001). In this paper we show significant expression of PDE6B, PDE6C, and PDE6D, in human breast cancer cell lines and patients’ breast cancer tissues
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
