Epidemiological studies demonstrate that high body mass index during puberty is associated with reduced lifetime breast cancer risk. It is suggested that increased abundance of adipose tissue in pubertal girls affects future breast cancer risk through reducing mammographic density, which is a major breast cancer risk factor. However, causal relationships are yet to be established. This project aimed to investigate the impact of increased pubertal adipose tissue deposition on mammary density and cancer development using the Alms null mouse model of adiposity and the Mmtv-Pymt transgenic model of mammary cancer.
Alms-/- mice overeat and exhibit increased weight gain by 5 weeks of age when fed a normal mouse diet. These mice were fed ad libitum until 7 weeks and then calorie-matched with wildtype mice thereafter such that adult Alms-/- mice weight was comparable to wildtype. Mammary glands were dissected from Alms-/-and wildtype Alms+/+ female mice during puberty (6 weeks; n=10/group) and adulthood (12 weeks; n=10/group) and fixed for histological assessment or frozen for cytokine assessment by Luminex. Mammary tumours were dissected from Alms mice crossed with Mmtv-Pymt mice (18 weeks; n=15/group).
At puberty, Alms-/-mice exhibited larger adipocytes than wildtype, and increased number of terminal end buds and proliferating epithelial cells. At adulthood, Alms-/- mice exhibited a 55% decrease in percent fibroglandular density, accompanied by elevated interleukin 6 and tumour necrosis factor alpha, compared to wildtype. At 18 weeks, Alms-/-xMmtv-PyMT mice exhibited a 60% decrease in tumour burden and tumour development was delayed compared to Alms+/+xMmtv-PyMT controls.
Together with epidemiological studies, these findings provide strong support for the notion that increased pubertal adipose tissue deposition is a key determinant of adult breast cancer risk through altering mammographic density. We propose that puberty is a critical time for breast development which establishes breast cancer risk for the life course.