Rodent Model for Human Ductal Carcinoma in Situ

Institution: University of California, Berkeley
Investigator(s): Satyabrata Nandi, Ph.D. -
Award Cycle: 2001 (Cycle VII) Grant #: 7IB-0025 Award: $100,000
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (2001)
Technical improvements in mammography have resulted in a great increase in the detection of ductal carcinomas in situ (DCIS) and lobular carcinomas in situ (LCIS). These breast lesions are proliferations of the epithelial cells lining the ducts and lobules, but unlike breast cancers, these cells have not invaded into adjoining tissues. There are many varieties of these lesions as characterized by the arrangement of cells and by genetic changes in those cells. It is difficult to predict which of these lesions are likely to progress to breast cancers and which lesions likely present little danger to the patient. Because of these difficulties in predicting outcome, there is no consensus on how these lesions should be treated. It is of major importance to identify and understand why some of these in situ lesions progress to a cancerous state and others do not.

Our goal is to develop a rodent model for DCIS and LCIS in which large numbers of lesions of different types could be induced and then characterized as to their potential to become cancers. Our hypothesis is that we should be able to generate lesions of different types by using hormones that promote the growth of ductal or lobule cells in combination with two agents, cholera toxin and keratinocyte growth factor, that promote the growth of cells within the ducts and lobules. Combinations of hormones plus either cholera toxin or keratinocyte growth factor will first be tested in rats to determine which combinations are best in causing the growth of cells within ducts or lobules. Those having the greatest amount of growth will then be treated with chemical carcinogens to immortalize and transform the proliferations. Selected lesions will be transplanted to other rats to determine their potential for becoming cancers. Lesions will be characterized as to their histological structure, their ability to become cancers, whether they require hormones for their growth or can grow independent of hormones.

We anticipate that a large number of different types of lesions with different capabilities to become cancer will be generated using the novel growth promoting agents. These lesions should provide a unique model for establishing which characteristics are important in determining the fate of different kinds of lesions. Future directions would be in the development of markers for the diagnosis, prognosis, and therapy for these lesions.


Final Report (2002)
Technical improvements in mammography have resulted in a great increase in the detection of ductal carcinomas in situ (DCIS) and lobular carcinomas in situ (LCIS). These breast lesions are proliferations of the epithelial cells lining the ducts and lobules, but unlike breast cancers, these cells have not invaded into adjoining tissues. There are many varieties of these lesions as characterized by the arrangement of cells and by genetic changes in those cells. It is difficult to predict which of these lesions are likely to progress to breast cancers and which lesions present little danger to the patient. Because of these difficulties in predicting outcome, there is no consensus on how these lesions should be treated. It is of major importance to identify and understand why some of these in situ lesions progress to a cancerous state and others do not.

Our goal was to develop a rodent model for DCIS and LCIS in which large numbers of lesions of different types could be induced and then characterized as to their potential to become cancers. Our hypothesis is that we should be able to generate lesions of different types by using hormones that promote the growth of ductal or lobule cells in combination with two agents, cholera toxin and keratinocyte growth factor, that promote the growth of cells within the ducts and lobules.

The Specific Aims were 1. Development of methods for the induction of DCIS and LCIS in inbred rats. 2. Characterization of lesions as to their neoplastic potential and hormone dependency.

Epidermal Growth Factor (EGF), cortisol (F), and cholera toxin (CT) either singly or in combination were tested for their ability to induce intra-ductal or intra-alveolar hyperplasia in seven-week-old female Lewis rats. EGF alone infused into the mammary glands through the nipple was able to induce intra-ductal hyperplasias within 24 hours after treatment, infusion of a combination of EGF, F, and CT resulted in the induction of intra-ductal hyperplasias, intra-alveolar hyperplasias, and lobular hyperplasia.

The next objective was to determine whether these hyperplasias would undergo transformation to mammary cancers when treated with a chemical carcinogen. The mammary glands on the right side of the rat were infused with EGF, the mammary glands on the left side were infused with a combination of EGF, F, and CT. Twenty-four hours later the rats were treated with a single injection of the chemical carcinogen, N-methyl-N-nitrosourea. Mammary tumors developed in 25% (4/16) mammary glands infused with a combination of EGF, F, and CT, 17% (2/12) mammary glands infused with EGF, and in 5% (1/20) glands infused with vehicle alone within two months after carcinogen treatment. The results indicate that it is feasible to induce intra-ductal and intra-alveolar hyperplasias and to transform them to mammary cancers by treatment with a chemical carcinogen.

In future studies, the infused mammary glands of carcinogen treated rats will be examined at earlier times prior to the appearance of mammary tumors to detect DCIS and LCIS and transplant them to the mammary fat pads of syngeneic rats to determine their potential to become malignant cancers and their hormone dependence. Homogenous transplant lines with different cancerous potential and hormone dependence will be developed. Genetic changes involved in the transition to malignant cancer will be determined by microarray technology.

Early diagnosis of DCIS and LCIS has led to improved survival. The optimum therapy for DCIS and LCIS has not been established. The current project might provide models for the better characterization of DCIS and LCIS. This could ultimately lead to the development of improved markers for diagnosis, prognosis or optimum therapy.