Journal of Mammary Gland Biology and Neoplasia

The discovery of multiple EGF-like ligands and erbB receptors offers the potential for a highly diverse signaling system allowing specific ligand/receptor complexes to be created in response to a certain hormone(s) or stage of mammary development. The known erbB receptors and several of the erbB-related ligands are synthesized by the normal mammary gland and have different temporal and spatial expression patterns. For instance, cumulative findings support the concepts that the EGF receptor has an essential role in morphogenesis of the mammary gland and that activation of this receptor occurs in response to estradiol-stimulated synthesis of an EGF receptor ligand in mammary stromal cells. The importance of both epithelial and stromal mammary cells in the hormonal activation of erbB-related pathways is underscored in this review. Current experimental protocols that utilize erbB mutant mice or enable detection of phosphorylated erbB members and their proximal substrates should permit more precise identification of the pathways operative in the mammary gland.

Smoking cigarettes is one of the most concerning issues that leads to tobacco-related cancers and can even result in death. Therefore, these issues should be addressed with a great sense of urgency with low-cost and simple approaches. Over the past several years, the scientific community has attempted to find solutions to overcome this issue. Thus, a large number of excellent studies have been reported in this field, and summarizing these results and providing important roadmaps for future studies is currently of great importance. Finding an outstanding solution to address aforementioned issue would be of great value to the community and to the social. Tobacco contains thousands of chemicals, and sixty-nine compounds have been established as human carcinogens; specifically, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the strongest carcinogen among the tobacco-specific nitrosamines. Tobacco carcinogens are also linked to mammary gland pathogenesis and increased risk of developing many cancers, including breast cancer, the most common cancer in women worldwide. This mini-review summarizes the role of NNK and the mechanisms of its receptor, nicotine acetylcholine receptor (nAChR), signaling in breast cancer based on publications identified using the keywords “secondhand smoke (SHS)”, “Nitrosamines” and “breast cancer”. Furthermore, this review considers the risk of NNK to the public in an effort to reduce exposure to SHS in women and their chances of developing breast cancer.

The innate immune system ensures effective protection against foreign pathogens and plays important roles in tissue remodeling. There are many types of innate immune cells, including monocytes, macrophages, dendritic cells, and granulocytes. Interestingly, these cells accumulate in most solid tumors, including those of the breast. There, they play a tumor-promoting role through secretion of growth and angiogenic factors, as well as immunosuppressive molecules. This is in strong contrast to the tumor-suppressing effects that innate immune cells exert in vitro upon proper activation. Therapeutic approaches have been developed with the aim of achieving similar suppressive activities in vivo. However, multiple factors in the tumor microenvironment, many of which are immunosuppressive, represent a major obstacle to effective treatment. Here, we discuss the potential of combating breast cancer through activation of the innate immune system, including possible strategies to enhance the success of immunotherapy.

Short-chain fatty acids activate antimicrobial component production in the intestine. However, their effects on mammary glands remain unclear. We investigated the effects of acetate and butyrate on antimicrobial component production in mammary epithelial cells (MECs) or leukocytes cultured in vitro and in mammary glands of lactating Tokara goats in vivo. Our results showed that butyrate enhanced the production of β-defensin-1 and S100A7 in MECs. Additionally, the infusion of butyrate into mammary glands through the teats enhanced β-defensin-1 and S100A7 concentrations in milk. The infusion of acetate also increased β-defensin-1 and S100A7 concentrations along with those of cathelicidin-2 and interleukin-8, which are produced by leukocytes. Furthermore, acetate promoted cathelicidin-2 and interleukin-8 secretion in leukocytes in vitro. These findings suggest that acetate and butyrate differentially upregulate antimicrobial component production in mammary glands, which could help to develop appropriate treatment for mastitis, thereby reducing economic losses and improving animal welfare in farming environments.

Genetic analyses of two hedgehog signal transduction network genes, Patched-1 and Gli2, has demonstrated a critical role for hedgehog signaling in mediating epithelial-stromal tissue interactions during ductal development. Disruption of either gene leads to similar, yet distinct, defects in ductal morphogenesis. Defects are mainly ductal dysplasias that closely resemble some hyperplasias of the human breast. Phenotypic analyses have been coupled with in situ hybridization, transplantation and tissue recombination analyses to formulate a model for tissue compartment-specific control of mouse mammary gland development by hedgehog signaling. In addition, the similarities among hedgehog mutation-induced ductal dysplasias and human breast pathologies suggest a role for altered hedgehog signaling in the development of mammary cancer.

It is well established that milk production of the dairy cow is a function of mammary epithelial cell (MEC) number and activity and that these factors can be influenced by diverse environmental influences and management practises (nutrition, milk frequency, photoperiod, udder health, hormonal and local effectors). Thus, understanding how the mammary gland is able to respond to these environmental cues provides a huge potential to enhance milk production of the dairy cow. In recent years our understanding of molecular events within the MEC underlying bovine lactation has been advanced through mammary microarray studies and will be further advanced through the recent availability of the bovine genome sequence. In addition, the potential of epigenetic regulation (non-sequence inheritable chemical changes in chromatin, such as DNA methylation and histone modifications, which affect gene expression) to manipulate mammary function is emerging. We propose that a substantial proportion of unexplained phenotypic variation in the dairy cow is due to epigenetic regulation. Heritability of epigenetic marks also highlights the potential to modify lactation performance of offspring. Understanding the response of the MEC (cell signaling pathways and epigenetic mechanisms) to external stimuli will be an important prerequisite to devising new technologies for maximising their activity and, hence, milk production in the dairy cow.

Metalloestrogens are metals that activate the estrogen receptor in the absence of estradiol. The metalloestrogens fall into two subclasses: metal/metalloid anions and bivalent cationic metals. The metal/metalloid anions include compounds such as arsenite, nitrite, selenite, and vanadate while the bivalent cations include metals such as cadmium, calcium, cobalt, copper, nickel, chromium, lead, mercury, and tin. The best studied metalloestrogen is cadmium. It is a heavy metal and a prevalent environmental contaminant with no known physiological function. This review addresses our current understanding of the mechanism by which cadmium and the bivalent cationic metals activate estrogen receptor-α. The review also summarizes the in vitro and in vivo evidence that cadmium functions as an estrogen and the potential role of cadmium in breast cancer.