AR is required for mammary differentiation and function during pregnancy/ lactation and tissue remodelling during mammary involution in female mice (#134)
Whether androgens influence lactation is not known; however, the expression of the androgen receptor (AR) in normal mammary cells of women and mice suggests a possible role for AR-mediated androgen action in mammary function. To gain insight into the role of AR in mammary gland, we used AR knockout (ARKO) female mice with complete androgen insensitivity.
We found that while AR has an inhibitory role in mammary gland during development (unpublished results), androgens via AR support mammary functional differentiation. In mid-pregnancy at gestation day 13, alveolar morphogenesis was delayed in ARKO mammary gland compared to WT (8±2 vs 14±3% of mammary fat pad occupied by alveoli p=0.053). The alveolar area was not affected by genotype during lactation (day 9; 70±4 vs 72±1%), but the lactating ARKO glands had larger alveolar lumen and fewer alveoli/mm2 (15±1 vs 20±1 number of alveoli, p=0.04). The suggestion of a functional impairment in ARKO mammary gland was supported by a reduced weight gain over 15 days from birth for pups (in litters of equal size) from ARKO compared to WT dams (11±0.3 vs 13 ±0.4 g body weight on day 15; p=0.01).
In addition, androgens via AR promote mammary involution. In ARKO mammary gland, alveolar regression was significantly delayed (45±6 vs 21±9% of alveoli still occupying fat pad, p=0.01) with distended alveoli at 3 days post-weaning. Yet, more apoptotic cells were present in ARKO glands compared to WT (16±3 vs 3±1% of Tunel-positive cells; stereology p=0.009). ARKO and WT females had comparable serum DHT and estradiol, while ARKO females had lower testosterone level on gestation day 13 (0.26±0.02 vs 0.45±0.06 ng/ml) and lower serum progesterone (p<0.05) at all 3 stages.
In conclusion, the present study provides evidence that AR-mediated androgen actions are required for mammary alveolar differentiation and modify tissue remodelling during mammary involution.