CCL2-driven inflammation increases mammary gland stromal density and cancer susceptibility in a transgenic mouse model.

Abstract Background Macrophages play diverse roles in mammary gland development and breast cancer. CC-chemokine ligand 2 (CCL2) is an inflammatory cytokine that recruits macrophages to sites of injury. Although CCL2 has been detected in human and mouse mammary epithelium, its role in regulating mammary gland development and cancer risk has not been explored. Methods Transgenic mice were generated wherein CCL2 is driven by the mammary epithelial cell-specific mouse mammary tumour virus 206 (MMTV) promoter. Estrous cycles were tracked in adult transgenic and non-transgenic FVB mice, and mammary glands collected at the four different stages of the cycle. Dissected mammary glands were assessed for cyclical morphological changes, proliferation and apoptosis of epithelium, macrophage abundance and collagen deposition, and mRNA encoding matrix remodelling enzymes. Another cohort of control and transgenic mice received carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA) and tumour development was monitored weekly. CCL2 protein was also quantified in paired samples of human breast tissue with high and low mammographic density. Results Overexpression of CCL2 in the mammary epithelium resulted in an increased number of macrophages, increased density of stroma and collagen and elevated mRNA encoding matrix remodelling enzymes lysyl oxidase (LOX) and tissue inhibitor of matrix metalloproteinases (TIMP)3 compared to non-transgenic controls. Transgenic mice also exhibited increased susceptibility to development of DMBA-induced mammary tumours. In a paired sample cohort of human breast tissue, abundance of epithelial-cell-associated CCL2 was higher in breast tissue of high mammographic density compared to tissue of low mammographic density. Conclusions Constitutive expression of CCL2 by the mouse mammary epithelium induces a state of low level chronic inflammation that increases stromal density and elevates cancer risk. We propose that CCL2-driven inflammation contributes to the increased risk of breast cancer observed in women with high mammographic density

Land use and aquatic biointegrity in the Blackfoot River watershed, Montana

Benthic macroinvertebrate samples representing 151 taxa were collected in August 1995 to examine the linkage between land use, water quality, and aquatic biointegrity in seven tributaries of the Blackfoot River watershed, Montana. The tributaries represent silvicultural (timber harvesting), agricultural (irrigated alfalfa and hay and livestock grazing), and wilderness land uses. A 2.4 km (1.5 mile) reach of a recently restored tributary also was sampled for comparison with the other six sites. A geographic information system (GIS) was used to characterize the seven subwatersheds and estimate soil erosion, using the Modified Universal Soil Loss Equation, and sediment delivery. The wilderness stream had the highest aquatic biointegrity. Two agricultural streams had the largest estimated soil erosion and sediment delivery rates, the greatest habitat impairment from nonpoint source pollution, and the most impoverished macroinvertebrate communities. The silvicultural subwatersheds had greater rates of estimated soil erosion and sediment delivery and lower aquatic biointegrity than the wilderness reference site but evinced better conditions than the agricultural sites. A multiple-use (forestry, grazing, and wildlife management) watershed and the restored site ranked between the silvicultural and agricultural sites. This spectrum of land use and aquatic biointegrity illustrates both the challenges and opportunities that define watershed management

Overview of mammary gland development: a comparison of mouse and human

The mouse mammary gland is widely used as a model for human breast cancer and has greatly added to our understanding of the molecular mechanisms involved in breast cancer development and progression. To fully appreciate the validity and limitations of the mouse model, it is essential to be aware of the similarities and also the differences that exist between the mouse mammary gland and the human breast. This introduction therefore describes the parallels and contrasts in mouse mammary gland and human breast morphogenesis from an early embryonic phase through to puberty, adulthood, pregnancy, parturition, and lactation, and finally the regressive stage of involution