Changes in mammary caveolin-1 signaling pathways are associated with breast cancer risk in rats exposed to estradiol in utero or during prepuberty.

Developmental stage of rat mammary gland at the time of estrogen exposure determines whether the exposure increases or reduces later breast cancer risk. For example, in utero exposure to 17β-estradiol (E2) increases, whereas prepubertal exposure to this hormone decreases susceptibility of developing carcinogen-induced mammary tumors. E2 mediates its actions by interacting with caveolin-1 (CAV1), a putative tumor suppressor gene in breast cancer. Mammary tissues from 2-month-old rats exposed to E2 in utero contained decreased levels of CAV1, whereas prepubertal E2 exposure increased the levels, when compared to vehicle controls. Low CAV1 expression was associated with increased cell proliferation and estrogen receptor α expression, and reduced apoptosis in the mammary glands of rats exposed to E2 in utero. In contrast, high CAV1 expression correlated with reduced cell proliferation and cyclin D1 and phospho-Akt levels, and increased apoptosis in the mammary glands of rats exposed to E2 during prepuberty. In support of the role of CAV1 as a negative regulator of a variety of pro-growth signaling proteins, we detected decreased levels of Src and ErbB2 in rats exposed to E2 during prepuberty. Thus, estrogen exposure during mammary gland development affects the expression and function of CAV1 in a manner consistent with observed changes in susceptibility to mammary tumorigenesis.