Homeobox Genes: A New Class of Human Breast Oncogenes?

Institution: University of California, Santa Cruz
Investigator(s): Michael Lewis, Ph.D. -
Award Cycle: 1996 (Cycle II) Grant #: 2FB-0047 Award: $70,000
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (1996)
A genetic basis for cancer in general, and for breast cancer in particular, is now well established. Present evidence indicates that cancer initiation and progression is associated with alterations in multiple genetic elements, some of which may be inherited, while others reflect mutations occurring later in life. Candidates for breast cancer genes now include a large class of developmental regulators known as homeobox genes, based on our recent discovery that some of these are expressed in the development of the mouse mammary glad and are misexpressed (inappropriately turned on or off) in mouse mammary cancer relative to the normal mouse mammary gland. Homeobox genes normally function to establish cell identity and to provide positional information to the cell for proper patterning of the body and its organs as an animal grows from a fertilized egg to an adult.

Because homeobox genes are known to be critically important in the normal development of organisms ranging from flies to humans, and because cancer is a consequence of normal development gone awry, mutations in these genes may contribute to cancer. Development is the controlled acquisition of cellular identity (differentiation) and patterning (morphogenesis) over time. Cancer, in contrast, is characterized by the loss of cellular identity, patterning, and growth control. Therefore, a mutation in a gene that regulates these processes might cause cells to lose their differentiated state and their normal ability to form or maintain patterned structures, thereby contributing to cancer.

We propose to extend our studies of homeobox genes into the clinical arena of human breast development and cancer. We will study tissue samples from patients who have had breast tumors surgically removed; these studies will determine which homeobox genes are turned on and whether certain homeobox gene products are misexpressed in these tumors relative to adjacent normal human breast tissue. We will also determine which kinds of cells normally contain homeobox genes which are turned on, and in which kinds of cells the homeobox genes are normally turned off.

These studies, in conjunction with experiments we will conduct of mouse mammary cancer, will address the questions of whether these important developmental regulatory genes are normally functional in the human breast tissue and whether these genes show altered function in breast tumors. This work is designed to lay the foundation for determining whether or not homeobox genes contribute to the initiation and/or malignant progression of human breast cancer. At the clinical level, homeobox genes may eventually serve as targets for therapeutic agents, gene therapy or for markers for detection of tumor onset and tumor progression.

Final Report (1998)
Candidates for breast-cancer genes now include a large class of developmental regulators known as homeobox genes. In this project we narrowed our focus to the family of IRX homeobox genes which we discovered-during the first year of-the project. We have extensively studied one family member, IRX-2. This data suggests that IRX genes play a critical role in mammary gland development and cancer. IRX genes appear to be related to a family of 'Iroquois-class' homeobox genes in fruit flies, which are regulated by a cell-cell signaling pathway called the hedgehog pathway. We are examining whether the mouse and human hedgehog pathway controls the expression of IRX genes in the breast. Importantly, many genes encoding vertebrate hedgehog pathway components are either known oncogenes or tumor suppressor genes. Therefore, the IRX may contribute to breast cancer.

Because it is impossible to experimentally assay function of human genes in living humans, we have developed a method for introducing human genes to mouse mammary gland cells followed by reconstitution of the normal ductal system. We have used this technique to assay function of the human HOXD10 and MSX1 genes in mammary cells. This gene introduction strategy should be adaptable to gene therapy and cell therapy strategies in human breast.

Finally, we have established a collaboration to use the new technology of DNA arrays for examining changes in HOX gene expression during cancer. Use of this technology allows us to simultaneously examine expression of more genes in a tissue than would otherwise be possible using our original approach.

Hedgehog signaling in mammary gland development.
Periodical:Journal of Mammary Gland Biology and Neoplasia
Index Medicus: J Mammary Gland Biol Neoplasia
Authors: MT Lewis
Yr: 2001 Vol: 6 Nbr: 1 Abs: Pg:53-66

Homeobox genes in mammary glad development and neoplasia.
Periodical:Breast Cancer Research and Treatment
Index Medicus: Breast Cancer Res Treat
Authors: MT Lewis
Yr: 2000 Vol: 2 Nbr: Abs: Pg:158-169

The Gli2 transcription factor is required for normal mouse mammary gland development.
Periodical:Developmental Biology
Index Medicus: Dev Biol
Authors: MT Lewis, S. Ross, P.A. Strickland, C. Sugnet, E. Jimenez, C-c Hui, and C.W. Daniel.
Yr: 2001 Vol: 238 Nbr: 1 Abs: Pg:133-44

Defects in mouse mammary gland development caused by conditional haploinsufficiency of Patched-1
Index Medicus:
Authors: Lewis MT, Ross S, Strickland PA, Sugnet CW, Jimenez E, Scott MP, Daniel CW.
Yr: 1999 Vol: 126 Nbr: 22 Abs: Pg:5181-93

Regulated expression patterns of IRX-2, an Iroquois-class homeobox gene, in the human breast.
Periodical:Cell Tissue Research
Index Medicus:
Authors: M.T. Lewis, S. Ross, P. A. Strickland, C.J. Snyder, and C.W. Daniel
Yr: 1999 Vol: 296 Nbr: Abs: Pg:549-554