Adrian Lee Laboratory
PROJECTS
My laboratory is investigating the role of cross-talk between steroid hormones and growth factors in the development of the mammary gland and progression to mammary cancer. The laboratory uses a multi-disciplinary approach including in vitro and in vivo applications employing state-of-the-art equipment. The main projects are listed below:
Hormone regulation of IGF signaling in breast cancer cell lines and tissue
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Several groups have now shown interactions between
steroid hormone receptors and growth factor signaling pathways. These interactions
may be critical for the development and progression of breast cancer, and
may also be relevant during treatment and resistance. 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. More recently we have shown that progesterone
can also sensitize cells to IGFs, via a specific induction of IRS-2 but
not IGF-IR or IRS-1. We are currently focusing on how estrogen and progesterone
induce transcription of these genes and what are the downstream biologic
consequences, including migration and invasion in breast cancer cell lines.
Role of IGF-IR and IRSs in normal mammary gland development and tumorigenesis
IGFs are critical for normal mammary gland development. 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. Our current studies are using knockout
and transgenic mice to understand the role of IGF-IR and IRSs in both normal
mammary gland development and the progression to mammary cancer.
Novel agents to block IGF action in breast cancer
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Evidence implicating the IGF system in breast
cancer cells as well as normal mammary gland development has led to many
strategies to block IGF action in breast cancer. We have previously utilized
a number of strategies including dominant-negative IGF-IR, dominant negative-IRS-1,
and overexpressed IGFBP-1 to block IGF action. We are now using newly developed
inhibitors of IGF action to determine the role of IGF and IGF-IR in breast
cancer progression.
Non-nuclear hormone receptor signaling.
Recent evidence suggests that estrogen receptor can directly bind and activate
elements of the IGF signaling cascade including IGF-IR, IRS-1, and PI3K.
We are using our ER-negative C4-12 cell line model to express mutant ERs
and decipher the role of these interactions with the IGF system in hormone
and growth factor interaction in breast cancer proliferation.
