Location: Immunity and Disease Prevention ResearchTitle: The transcriptome of estrogen-independent mammary growth reveals that not all mammary glands are created equally Author
Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/21/2017
Publication Date: 7/27/2017
Citation: Berryhill, G.E., Lemay, D.G., Trott, J.F., Aimo, L., Lock, A.L., Hovey, R.C. 2017. The transcriptome of estrogen-independent mammary growth reveals that not all mammary glands are created equally. Endocrinology. doi: 10.1210/en.2017-00395. Interpretive Summary: An earlier onset of breast growth during puberty increases the lifetime risk of breast cancer. While it was believed that breast growth depended on the hormone, estrogen, we recently discovered that a dietary component can increase mammary gland growth in the absence of estrogen. The dietary component is the fatty acid, trans-10, cis-12 conjugated linoleic acid (CLA). In the current study, we used a rodent model to understand how dietary CLA affects mammary growth at the molecular level. Estrogen and CLA each induced mammary growth but the genes expressed in the mammary gland to achieve that growth were different. Unlike estrogen, CLA increased expression of inflammatory response genes within the mammary gland. While this study was conducted in a mouse model, the research demonstrates that diet can induce inflammation that increases breast growth in the absence of estrogen. This will inform future work to prevent and/or treat estrogen-independent breast cancers.
Technical Abstract: Allometric growth of ducts in the mammary glands (MG) is widely-held to be estrogen (E)-dependent. We previously discovered that the dietary fatty acid trans-10, cis-12 conjugated linoleic acid (CLA) stimulates E-independent allometric growth and TEB formation in ovariectomized mice. Given the similar phenotype induced by E and CLA, we investigated the shared and/or divergent mechanisms underlying these changes. We confirmed MG growth induced by CLA is temporally distinct from that elicited by E. Using RNA-Sequencing we compared the transcriptome of the MG during similar proliferative and morphological states. Both E and CLA impacted genes involved in proliferation. The MG transcriptome for E-treated mice included canonical E-induced genes including Pgr, Areg, and Foxa1, whereas their expression was unchanged by CLA. By contrast, CLA, but not E, altered expression of a unique set of inflammation-associated genes, consistent with changes in the stroma. This CLA-altered signature included increased expression of epidermal growth factor receptor (EGFR) pathway components, consistent with the demonstration that CLA-induced MG growth is EGFR dependent. Our findings highlight a unique role for diet-induced inflammation that underlies E-independent MG development. Our results also provide the complete transcriptome of E-induced allometric growth.