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Clinical Research Institute at Rambam (CRIR), Division of Endocrinology, Diabetes and Metabolism Clinical Research Center of Excellence, Rambam Medical Center, PO Box 9602, Haifa 31096, Israel
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Obesity and type 2 diabetes (T2D) are associated with an increased risk of breast cancer incidence and mortality. Common features of obesity and T2D are insulin resistance and hyperinsulinemia. A mammary tumor promoting effect of insulin resistance and hyperinsulinemia was demonstrated in the transgenic female MKR mouse model of pre-diabetes inoculated with mammary cancer cells. Interestingly, in MKR mice, as well as in other diabetic mouse models, males exhibit severe hyperglycemia, while females display insulin resistance and hyperinsulinemia with only a mild increase in blood glucose levels. This gender-specific protection from hyperglycemia may be attributed to estradiol, a key player in the regulation of the metabolic state, including obesity, glucose homeostasis, insulin resistance, and lipid profile. The aim of this study was to investigate the effects of ovariectomy (including the removal of endogenous estradiol) on the metabolic state of MKR female mice and subsequently on the growth of Mvt-1 mammary cancer cells, inoculated into the mammary fat pad of ovariectomized mice, compared with sham-operated mice. The results showed an increase in body weight, accompanied by increased fat mass, elevated blood glucose levels, and hypercholesterolemia, in ovariectomized MKR mice. In addition, mammary tumor growth was significantly higher in these mice. The results suggest that ovarian hormone deficiency may promote impaired metabolic homeostasis in the hyperinsulinemic MKR female mice, which in turn is associated with an increased growth of mammary tumors.
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
Search for other papers by Derek LeRoith in
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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The role of circulating IGF-I in skeletal acquisition and the anabolic response to PTH is not well understood. We generated IGF-I-deficient mice by gene deletions of IGF ternary complex components including: (1) liver-specific deletion of the IGF-I gene (LID), (2) global deletion of the acid-labile (ALS) gene (ALSKO), and (3) both liver IGF-I and ALS inactivated genes (LA). Twelve-week-old male control (CTL), LID, ALSKO, and LA mice were treated with vehicle (VEH) or human PTH(1–34) for 4 weeks. VEH-treated IGF-I-deficient mice (i.e. LID, ALSKO and LA mice) exhibited reduced cortical cross-sectional area (P = 0.001) compared with CTL mice; in contrast, femoral trabecular bone volume fractions (BV/TV) of the IGF-I-deficient mice were consistently greater than CTL (P<0.01). ALSKO mice exhibited markedly reduced osteoblast number and surface (P<0.05), as well as mineral apposition rate compared with other IGF-I-deficient and CTL mice. Adherent bone marrow stromal cells, cultured in β-glycerol phosphate and ascorbic acid, showed no strain differences in secreted IGF-I. In response to PTH, there were both compartment- and strain-specific effects. Cortical bone area was increased by PTH in CTL and ALSKO mice, but not in LID or LA mice. In the trabecular compartment, PTH increased femoral and vertebral BV/TV in LID, but not in ALSKO or LA mice. In conclusion, we demonstrated that the presentation of IGF-I as a circulating complex is essential for skeletal remodeling and the anabolic response to PTH. We postulate that the ternary complex itself, rather than IGF-I alone, influences bone acquisition in a compartment-specific manner (i.e. cortical vs trabecular bone).
