Diet-induced metabolic change induces estrogen-independent allometric mammary growth

Grace E. Berryhill, Julia M. Gloviczki, Josephine F. Trott, Lucila Aimo, Jana Kraft, Robert Cardiff, Carly T. Paul, Whitney K. Petrie, Adam L. Lock, Russell C. Hovey

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18 Scopus citations

Abstract

Lifetime breast cancer risk re flects an unresolved combination of early life factors including diet, body mass index, metabolic syndrome, obesity, and age at first menses. In parallel, the onset of allometric growth by the mammary glands around puberty is widely held to be estrogen (E)-dependent. Here we report that several physiological changes associated with metabolic syndrome in response to a diet supplemented with the trans-10, cis-12 isomer of conjugated linoleic acid lead to ovary-independent allometric growth of the mammary ducts. The E-independence of this diet-induced growth was highlighted by the fact that it occurred both in male mice and with pharmacological inhibition of either E receptor function or E biosynthesis. Reversal of the metabolic phenotype with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone abrogated diet-induced mammary growth. A role for hyperinsulinemia and increased insulin-like growth factor-I receptor (IGF-IR) expression during mammary growth induced by the trans-10, cis-12 isomer of conjugated linoleic acid was confirmed by its reversal upon pharmacological inhibition of IGF-IR function. Diet-stimulated ductal growth also increased mammary tumorigenesis in ovariectomized polyomavirus middle T-antigen mice. Our data demonstrate that diet-induced metabolic dysregulation, independently of ovarian function, stimulates allometric growth within the mammary glands via an IGF-IR-dependent mechanism.

Original languageEnglish (US)
Pages (from-to)16294-16299
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number40
DOIs
StatePublished - Oct 2 2012

ASJC Scopus subject areas

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    Berryhill, G. E., Gloviczki, J. M., Trott, J. F., Aimo, L., Kraft, J., Cardiff, R., Paul, C. T., Petrie, W. K., Lock, A. L., & Hovey, R. C. (2012). Diet-induced metabolic change induces estrogen-independent allometric mammary growth. Proceedings of the National Academy of Sciences of the United States of America, 109(40), 16294-16299. https://doi.org/10.1073/pnas.1210527109