Discussion After many years of debate, there is now ample proof that tobacco smoke increases the risk of breast cancer. Multiple studies, including some published after the last Surgeon General Report and IARC monographs on the subject show that active and passive exposure to tobacco smoke increases the risk of breast cancer selleck kinase inhibitor in both premenopausal and postmenopausal women. With the epidemiological evidence Inhibitors,Modulators,Libraries now conclusive, the task remains to investigate the molecular mechanism by which exposure to tobacco smoke, either voluntary or involuntary, leads to increased breast cancer risk. The response of breast epithelial cells and breast cancer cell to cigarette smoke has been previously examined, but these studies focused on short term treatment while we have analyzed the ef fect of continuous long term exposure.
We demonstrated that chronic exposure to tobacco smoke in the form of CSE or CSC can alter the phenotype of mammary epithe lial cells, promoting the acquisition of mesenchymal traits such as increased anchorage independent growth, motility, invasion, and the Inhibitors,Modulators,Libraries expression of markers associated with self renewal and tumor initiation. Numerous groups have demonstrated the emergence of a CD44 CD24 low stem like signature from CD44 lowCD24 cells upon the induction of an EMT phenotype characterized by loss of E cadherin and gain of vimentin. The CD44 CD24 low phenotype has been consistently asso ciated with self renewing mammary epithelial cells, which are also more tumorigenic and basal like than CD44 CD24 cells.
Similarly, we showed that treatment of MCF 10A cells with Inhibitors,Modulators,Libraries CSE leads to the emer gence of a CD44hiCD24low population, and our in vivo experiments demonstrated that CSE treated MCF 10A cells have increased Inhibitors,Modulators,Libraries survival and colonization ability. Although MCF 10A cells did not become malignant, treatment of the MCF7 cancer cell line led to increased metastatic potential, consistent with published evidence that the differentiation state of the cell of origin is a strong determinant of the cellular phenotype of the final transformed state. Other studies in animal models have previously shown that tobacco smoke can increase the risk of metastasis from breast cancer, but this has been attributed mainly to smoking induced inhibition of host antitumor immune defenses, or to damage of the host tissue. In contrast, our data from ex vivo ex posure followed by orthotopic or subcutaneous transplant ation into mice indicate that Inhibitors,Modulators,Libraries tobacco smoke can directly affect the ability of breast epithelial cells to invade or metastasize, independent of Dovitinib solubility other cigarette smoke effects on the host and stromal environment.