High mammographic density is an independent risk factor for breast cancer. Epidemiological studies show that high body mass index in puberty is associated with low adult mammographic density and reduced lifetime breast cancer risk. This suggests that pubertal adiposity affects adult breast health, however, causal mechanisms are yet to be elucidated. This project investigated whether pubertal adiposity is causal in mammary fibroglandular density and cancer development in adulthood using mouse models.
Alms1bbb/bbb mice overeat and exhibit increased weight gain than wildtype when fed a normal mouse diet. Mammary glands were dissected from Alms1bbb/bbb and wildtype female mice during puberty (6 weeks; n=10/gp). To determine the impact of pubertal adiposity on mammary density, Alms1bbb/bbb mice were calorie-matched with wildtype from 7 weeks of age, such that weight of adult Alms1bbb/bbb mice was comparable to that of wildtype. Mammary glands were then dissected from calorie-restricted Alms1bbb/bbb (and controls) at adulthood (12 weeks; n=10/gp). Alms mice were crossed with Mmtv-PyMT tumour mouse model (18 weeks; n=15/gp) to determine the impact of pubertal adiposity on mammary tumour development.
At puberty, Alms1bbb/bbb mice exhibited increased number of terminal end buds and proliferating epithelial cells compared to wildtypes, as well as larger adipocytes and increased number of macrophages around terminal end buds and in the mammary adipose tissue. At adulthood, Alms1bbb/bbb mice exhibited a 56% decrease in fibroglandular density, accompanied with reduced stroma and collagen deposition, compared to wildtype. A 46% decrease in tumour burden and delayed tumour development was observed in Alms1bbb/bbb-PyMT mice, compared to control-PyMT mice.
Our findings indicate that increased adiposity during puberty reduces both mammary fibroglandular density and cancer development in adulthood. Together with epidemiological studies, this research provides the foundation for a new paradigm for the origins of mammographic density and breast cancer risk during pubertal mammary gland development.