We are investigating the endocrine regulation of mammary gland development and progression to mammary cancer. Specifically we are interested in interaction between steroid hormones (estrogen and progesterone) with the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. These endocrine hormones are all critical for normal mammary development, but have also all been implicated in risk for breast cancer and in breast cancer progression.

We have shown that IGF-IR and IRSs are hormonally regulated in breast cancer, and we have now found that they are also developmentally and hormonally regulated during normal mammary gland development. We have found in breast cancer cell lines that estrogen can sensitize cells to insulin-like growth factor (IGF) stimulation by increasing expression of many of the IGF signaling components such as the IGF-IR and its downstream signaling intermediates IRS-1 and IRS-2.

We have also found that overexpression of IGF-IR, IRS-1, or IRS-2 causes transformation of mammary epithelial cells in culture, combined with epithelial to mesenchymal transition. We have also created transgenic mice that overexpress IGF-IR, IRS-1 or IRS-2 in the mammary gland and all mice develop mammary tumors. Mammary tumors in these mice show multiple cell lineages and expansion of putative mammary stem/progenitor cells. We are currently investigating how these pathways impact upon stem/progenitor cell renewal and cell fate determination.

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Important Publications

Gualberto A, M Dolled-Filhart, M Gustavson, JJ Christiansen, YF Wang, ML Hixon, JM Reynolds, S McDonald, A Ang, DL Rimm, C Langer, J Blakely, LL Garland, L Paz-Ares, DD Karp and AV Lee.  Molecular analysis of non-small cell lung cancer (NSCLC) identifies subsets with different sensitivity to insulin like growth factor I receptor (IGF-IR) inhibition.  Clin Cancer Res, Epub ahead of print, 2010.

Dearth RK, DA Delgado, JK Hiney, T Pathiraja, S Oesterreich, D Medina, WL Dees and AV Lee.  Parity-induced decrease in systemic growth hormone alters mammary gland signaling:  A potential role in pregnancy protection from breast cancer.  Cancer Prev Res 3:312-321, 2010.

Creighton CJ, X Fu, BT Hennessy, AJ Casa, Y Zhang, AM Gonzalez-Angulo, A Lluch, JW Gray, PH Brown, SG Hilsenbeck, CK Osborne, GB Mills, AV Lee and R Schiff.  Proteomic and transcriptomic profiling reveals a link beween the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER+ breast cancer.  Breast Cancer Res 12:R40, 2010.

Hassan AA, TB Chan, KB Hartman, JS Ananta, Y Mackeyev, L Hu, RG Pautler, LJ WIlson and AV Lee.  Serine-derivatized gadonanotubes as magnetic nanoprobes for intracellular labeling of breast cancer cells.  Contrast Media and Molecular Imaging 5:34-38, 2010.

Migliaccio I, CK Osborne, C Gutierrez, DC Allred, S Mohsin, SG Hilsenbeck and AV Lee.  Nuclear IRS-1 predicts tamoxifen response in early breast cancer.  Breast Cancer Research and Treatment, in press, 2009.

Hampton OA, P Den Hollander, CA Miller, RA Harris, S Richards, SE Scherer, DM Muzny, RA Gibbs, AV Lee and A Milosavljevic.  A sequence-level map of chromosal breakpoints in the MCF-7 cancer cell line yields insights into the evolution of a cancer genome.  Genome Res 19:167-177, 2009.

Liu S, M Umezu-Goto, M Murph, Y Lu, W Liu, F Zhang, X Cui, G Murrow, K Coombes, W Muller, MC Hung, CM Perou, AV Lee, X Fang and GB Mills.  Expression of autotaxin and lysophosphatidic acid receptors increases mammary tumorigenesis, invasion, and metastases.  Cancer Cell 15:539-550, 2009.