Adolescent- and adult-initiated alcohol exposure in mice differentially promote tumorigenesis and metastasis of breast cancer.

BACKGROUND
Alcohol exposure increases the risk of breast cancer. Alcohol consumption is a serious social and public health issue for adolescents. This study investigated the impact of adolescent alcohol consumption on mammary tumorigenesis and progression and compared it to that of adult alcohol exposure in animal models.


METHODS
Female adolescent (5 weeks) and adult (8 weeks) MMTV-Wnt1 mice were exposed to alcohol either chronically or acutely. For chronic alcohol exposure, animals were fed with a liquid diet containing 6.7% ethanol for 23 weeks. For acute exposure, animals were treated with alcohol (2.5 g/kg, 25% w/v) via intraperitoneal (IP) injection for 15 days.


RESULTS
In control animals, the tumor latency was 18.5-22 weeks. Both chronic and acute alcohol exposure in adolescent mice significantly shortened the tumor latency to 9.5 and 8.4 weeks, respectively. However, adult-initiated alcohol exposure had little effect on the tumor latency. Both adolescent- and adult-initiated alcohol exposure significantly increased lung metastasis. Adolescent-initiated alcohol exposure but not adult-initiated alcohol exposure increased breast cancer stem cell population. Adolescent-initiated alcohol exposure significantly altered the proliferation of mammary epithelial cells, ductal growth, and the formation of terminal end buds in the mammary glands. Adolescent-initiated alcohol exposure but not adult-initiated alcohol exposure increased the estradiol levels in the blood. Acute adolescent alcohol exposure also significantly increased progesterone levels. Furthermore, adolescent-initiated alcohol exposure activated PAK1 and p38γ MAPK which are critical regulators of mammary tumorigenesis and aggressiveness, respectively, while adult-initiated alcohol exposure only activated p38γ MAPK. In addition, both adolescent and adult alcohol significantly decreased the levels of a prognostic marker miR200b.


CONCLUSIONS
Adolescent-initiated alcohol exposure enhanced both tumorigenesis and aggressiveness of mammary tumors, while adult-initiated alcohol exposure mainly promoted tumor metastasis. Thus, adolescent mice were more sensitive than adult mice in response to alcohol-induced tumor promotion.