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Developmental and Hormonal Signals Dramatically Alter the Localization and Abundance of Insulin Receptor Substrate Proteins in the Mammary Gland

The Breast Center, Departments of Medicine, Molecular and Cellular Biology, Pediatrics, and Pathology, Baylor College of Medicine, Houston, Texas 77030; U.S. Department of Agriculture/Agricultural Research Service, Children’s Nutrition Research, Center (S.B., D.L.H.), and Molecular and Cellular Endocrinology Section, Center for Cancer Research, National Cancer Institute (R.C.H., B.K.V.), National Institutes of Health, Bethesda, Maryland 20892; and Research Division, Joslin Diabetes Center, Department of Medicine, Harvard Medical School (C.R.K.), Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Adrian V. Lee, Ph.D., The Breast Center, Room N1110, Baylor College of Medicine, One Baylor Plaza, MS 600, Houston, Texas 77030. E-mail: avlee{at}breastcenter.tmc.edu.

Insulin receptor substrates (IRS) are central integrators of hormone, cytokine, and growth factor signaling. IRS proteins can be phosphorylated by a number of signaling pathways critical to normal mammary gland development. Studies in transgenic mice that overexpress IGF-I in the mammary gland suggested that IRS expression is important in the regulation of normal postlactational mammary involution. The goal of these studies was to examine IRS expression in the mouse mammary gland and determine the importance of IRS-1 to mammary development in the virgin mouse. IRS-1 and -2 show distinct patterns of protein expression in the virgin mouse mammary gland, and protein abundance is dramatically increased during pregnancy and lactation, but rapidly lost during involution. Consistent with hormone regulation, IRS-1 protein levels are reduced by ovariectomy, induced by combined treatment with estrogen and progesterone, and vary considerably throughout the estrous cycle. These changes occur without similar changes in mRNA levels, suggesting posttranscriptional control. Mammary glands from IRS-1 null mice have smaller fat pads than wild-type controls, but this reduction is proportional to the overall reduction in body size. Development of the mammary duct (terminal endbuds and branch points) is not altered by the loss of IRS-1, and pregnancy-induced proliferation is not changed. These data indicate that IRS undergo complex developmental and hormonal regulation in the mammary gland, and that IRS-1 is more likely to regulate mammary function in lactating mice than in virgin or pregnant mice.

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