The Chodosh laboratory uses genetically engineered mouse models to study the genes and mechanisms that cause breast cancer and that regulate normal mammary gland development. The relationship between mammary development and breast cancer susceptibility is illustrated by the observation that women who have their first child early in life have a significantly lower lifetime risk of developing breast cancer.
Understanding the molecular biology of breast cancer susceptibility requires a thorough understanding of the normal developmental biology of the mammary gland, the mechanisms by which breast cancers arise, and the role played by key regulatory molecules in each of these processes. Current experimental approaches towards these goals in the Chodosh laboratory include:
1. creating genetically engineered mouse models in which specific oncogenic pathways can be inducibly activated or repressed;
2. using INDUCIBLE ANIMAL MODELS to analyze the effect of developmental events on the mammary gland's response to a defined oncogenic stimulus;
3. using INDUCIBLE ANIMAL MODELS to dissect the process of carcinogenesis;
4. defining the molecular and cellular changes that occur in the mammary glands of mice, rats, and humans during STAGES OF DEVELOPMENT THAT INFLUENCE BREAST CANCER RISK;
5. using GENOMIC AND COMPUTATIONAL APPROACHES to investigate genetic programs in mammary development and carcinogenesis; and
6. studying the FUNCTION OF THREE NOVEL SERINE/THREONINE KINASES IN MAMMARY DEVELOPMENT AND CARCINOGENESIS. These approaches employ a variety of molecular, cellular, animal, human, and in silico model systems to study the function of key regulatory molecules in mammary gland biology.
This transgenic mouse system uses the MMTV-LTR to drive expression of the reverse tetracycline-dependent transactivator rtTA. Transgene expression using this system can be rapidly induced and deinduced, is highly mammary specific, can be reproducibly titrated over a wide range of expression levels, and is essentially undetectable in the uninduced state. This system permits transgene expression to be restricted to any desired stage of postnatal mammary gland development.
Restriction fragments containing the transgene MMTV-rtTA-pA were isolated from vector sequences and prepared for microinjection into fertilized oocytes. The transgenic lines was created on an inbred FVB/N background.
Transgene expression was induced in mice by replacing normal drinking water with 5% sucrose containing doxycycline.
This is a doxycycline-inducible bitransgenic mouse model for HER2/neu-induced mammary carcinogenesis. The tetracycline regulatory system is used to conditionally express activated Neu in the mammary epithelium of transgenic mice. These mice were generated by mating mice harboring the TetO-NeuNT transgene with MMTV-rtTA transgenic mice (MTB).
This model displays many features of human tumor progression, including invasion, metastasis, and recurrence.
"The transgene consists of the tet operator driving expression of a bicistronic transcript encoding activated rat Erbb2 (Neu), having the Val664Leu missense mutation, and firefly luciferase, the latter translated from an internal ribosome binding sequence (IRES) upstream of its coding sequence. In a mouse bitransgenic for this transgene and a tetracycline transactivator transgene, administration of doxycycline reversibly induces expression of Erbb2 and luciferase in tissues where the transactivator is expressed."