Estrogen receptor signalling in mammary epithelial cells

The mammary gland is a complex tissue going through cycles of extensive proliferation and differentiation. Many hormones are involved in the regulation of development of the mammary gland, including estrogen, prolactin and epidermal growth factor (EGF). The mouse HC 11 cell line is a well-studied model for mammary epithelial cells, unique in its ability to express milk proteins upon manipulation of medium conditions and subsequent lactogenic hormone treatment.

During the proliferation phase HC 11 cells are exposed to epidermal growth factor (EGF) and in order to initiate differentiation EGF is removed from the cells. In the present work, HC 11 cells were found to express estrogen receptors alpha (ERalpha) and beta (ERbeta). In differentiated HC 11 cells, i.e. cells able to express milk proteins, estrogen activation of ER resulted in downregulation of prolactin-induced beta-casein transcription. This was found to be due to protein-protein interaction between ER and the prolactin-activated transcription factor STAT5.

Furthermore, we found that ER transcriptional activity fluctuated through the differentiation process in HC 11 cells, with efficient estrogen-induced activation of transcription in proliferating cells and a significant decrease in ER transcriptional activity when the cells started to differentiate, i.e. when EGF was removed from the medium. Inhibition of a downstream mediator of EGF signalling in proliferating cells also decreased ER transcriptional activity. In addition, expression of known ER co-repressors, SHP and DAX-1, was increased when EGF was removed from HC 11 cells, correlating with the abolished ER transcriptional activity.

Studies on mice mammary glands confirmed the results from HC 11 cells, with low expression of DAX-1 in the virgin gland and a substantial increase in DAX-1 content in the lactating gland. Furthermore, the two ER subtypes was shown to have opposing actions in HC 11 cells upon estrogenic treatment. Stimulation of ERalpha signalling increased proliferation, while enhanced ERbeta signalling led to increased apoptosis.

List of scientific papers

I. Hedengran Faulds M, Pettersson K, Gustafsson JA, Haldosen LA (2001). Cross-talk between ERs and signal transducer and activator of transcription 5 is E2 dependent and involves two functionally separate mechanisms. Mol Endocrinol. 15(11): 1929-40.
https://pubmed.ncbi.nlm.nih.gov/11682624

II. Hedengran Faulds M, Olsen H, Helguero LA, Gustafsson JA, Haldosen LA (2004). Estrogen receptor functional activity changes during differentiation of mammary epithelial cells. Mol Endocrinol. 18(2): 412-21. Epub 2003 Nov 06
https://pubmed.ncbi.nlm.nih.gov/14605098

III. Hleguero LA, Hedengran Faulds M, Forster C, Gustafsson JA, Haldosen LA (2004). DAX-1 is negatively rehulated by EGF and determines estrogen responsiveness during mouse mammary gland differentiation. [Manuscript]

IV. Hleguero LA, Hedengran Faulds M, Gustafsson JA, Haldosen LA (2004). ERalpha and ERbeta differentially regulate proliferation and apoptosis of the normal murine mammary epithelial cell line HC11. [Manuscript]