> Research & Grants
> Grants Program
> Research Grants
> Research Grants Awarded
Research Grants Awarded
Residual Disease and Recurrence in Neu-induced Breast Cancer
Amplification and overexpression of the proto-oncogene HER2/Neu occurs in 15-30% of primary human breast cancers and is associated with aggressive tumor behavior, high rates of relapse, and poor prognosis. However, the molecular basis responsible for the aggressive behavior is unknown. To better define the role of Neu in mammary carcinogenesis and tumor progression we have created a novel bitransgenic mouse model in which Neu can be conditionally expressed in the mammary epithelium of animals treated with tetracycline derivatives. Following induction with doxycycline, bitransgenic animals develop invasive mammary adenocarcinomas, as well as extensive pulmonary metastases. Upon withdrawal of doxycycline, virtually all Neu-induced primary tumors and metastases regress to a clinically undetectable state, demonstrating that the malignant cells in the mammary tumors and sites of metastases remain dependent on Neu for the transformed state. However, the majority of mice bearing fully-regressed, Neu-induced mammary tumors ultimately develop spontaneous tumor recurrences in the absence of Neu expression. This indicates that these animals harbor residual neoplastic cells that are able to reestablish the malignant phenotype independent of Neu transgene expression. We hypothesize that detailed analysis of residual neoplastic cells and the signaling pathways that permit these cells to persist and ultimately recur following tumor regression, will facilitate the identification of genetic and biochemical pathways that lead to tumor recurrence. The specific aims of this proposal are to: I. Identify and analyze residual neoplastic cells that persist in the mammary gland and at distant sites in animals bearing fully regressed tumors; and II. Identify molecular pathways that become activated in residual neoplastic cells that contribute to tumor recurrence. We believe that this animal model provides a valuable opportunity for examining the genetic and molecular events that contribute to the establishment of residual neoplastic disease and the recurrence of Neu-induced mammary tumors. The identification of secondary pathways that contribute to the recurrence of Neu-induced tumors should facilitate targeting of those pathways that are most critical in tumor progression and recurrence and in doing so will enhance the development of targeted therapeutic agents against this most aggressive form of breast cancer.
Among the more than 5 million women currently living with a diagnosis of breast cancer worldwide, tumor dormancy followed by recurrence represents the most common cause of death from this disease. While recurrence constitutes a problem of unparalleled clinical importance, little is known about the underlying mechanisms. A limited number of clinical and molecular characteristics of breast cancers have been shown to correlate with relapse-free survival. For example, breast cancer patients whose tumors overexpress the HER2/Neu protein display aggressive tumor behavior, decreased relapse-free survival, and overall poor prognosis. However, neither HER2/Neu nor other molecular prognostic markers have been shown to play a causal role in breast cancer recurrence. To identify the mechanisms involved in breast cancer recurrence, we have developed a novel transgenic mouse model that permits an activated version of Neu to be turned on in the mammary glands of transgenic mice when treated with the antibiotic doxycycline. These animals develop multiple invasive mammary adenocarcinomas that metastasize to the lung, yet after withdrawal of doxycycline and down-regulation of the HER2/Neu pathway, both mammary tumors and lung metastases regress to a clinically undetectable state. Many of these fully regressed mammary tumors spontaneously recur at their original site over periods of up to one year after full tumor regression. This suggests that residual cancerous cells remain at the site of regressed tumors that can ultimately give rise to recurrences and demonstrates that this model recapitulates key features of the natural history of human breast cancer. We hypothesize that detailed analysis of residual neoplastic cells and the signaling pathways that permit these cells to persist and ultimately recur, following tumor regression will facilitate the identification of genetic and biochemical pathways that lead to tumor recurrence. The specific aims of this study are to identify and analyze residual neoplastic cells that persist in the mammary gland and at distant sites in animals bearing fully regressed tumors, and to identify molecular pathways that become activated in residual neoplastic cells that contribute to tumor recurrence. In paralleling the behavior of human breast cancers, this animal model provides opportunity to improve the treatment of aggressive breast cancers.