Transforming growth factor-a (TGF-a) stimulates while TGF-b inhibits mammary epithelial cell growth, suggesting that when cells are treated concurrently with the growth factors their combined effects would result in no net growth. However, combined treatments stimulate proliferation and cellular transformation in several cell lines. The objective of this paper was to describe the effect of long-term (6 days) concurrent TGF-a and TGF-b treatment on normal mammary epithelial cell growth pattern, morphology, and gene expression. Growth curve analysis showed that TGF-a enhanced while TGF-b suppressed growth rate until Day 4, when cells entered lag phase. However, cells treated concurrently with both growth factors exhibited a dichotomous pattern of growth marked by growth and death phases (with no intermittent lag phase). These changes in growth patterns were due to a marked induction of cell death from Day 2 (16.5%) to Day 4 (89.5%), resulting in the transition from growth to death phases, even though the combined treated cultures had significantly more (P < 0.05) cells in S phase on Day 4. TGF-b stimulated epithelial to mesenchyme transdifferentiation (EMT) in the presence of TGF-a, as characterized by increased expression of fibronectin and changes in TGF-b receptor binding. Expression patterns of genes that regulate the cell cycle showed significant interaction between treatment and days, with TGF-b overriding TGF-a-stimulated effects on gene expression. Overall, the combined treatments were marked by enhanced rates of cellular proliferation, death, and transdifferentiation, behaviors reminiscent of breast tumors, and thus this system may serve as a good model to study breast tumorigenesis.

Mammary growth and development in heifers and cows is regulated by a complex interaction of multiple stimuli, including environmental, nutritional, and endocrine factors. The action of these various stimuli is mediated by a host of growth factors, including transforming growth factor-beta (TGF-β). TGF-β is a potent inhibitor of mammary epithelial cell growth and regulates extracellular matrix composition. TGF-β is expressed during bovine mammary development and its expression is particularly high at times of mammary growth and reorganization. The purpose of this paper is to review what we know about TGF-β and mammary growth and to explain how TGF-β affects the cell cycle in a normal epithelial cell line.