Novel Mechanisms Governing Human Breast Cancer Chromosomal Instability
Abstract
The abundance of cyclin D1 is increased in the majority human breast cancers and is overexpressed early in the disease, including ductal carcinoma in situ. Studies from many laboratories, including my own, have led to the understanding that cyclin D1 overexpression drives breast cancer. The currently accepted model is that increased cyclin D1 drives tumor growth through binding to a partner protein (Cdk) to form an enzyme that has kinase activity. It is widely believed that it is the kinase activity that drives the growth of many cancers including human breast cancer. Such studies have led to the development of drugs that effectively block cyclin D1 enzyme activity (Palbociclib, Ribociclib, Abemaciclib, G1T28, G1T38). Of concern, however, were the findings that, although these drugs efficiently reduce the kinase activity of cyclin D1, only a small proportion of patients had any response to monotherapy. Secondly, only a subset of all breast cancer patients (postmenopausal ERalpha+/Her2-) responded to Cdk inhibitors, even though the enzyme activity is increased in all genetic subtypes of breast cancer. Thirdly, response to Cdk inhibitors was observed only in combination therapy (with the addition of Cdk inhibitor to endocrine therapy inhibitors). Fourthly, all, patients treated with the kinase inhibitors progressed despite the inhibition of kinase activity. Although the mechanisms responsible for breast cancer progression in all patients treated with cdk inhibitors warrants further study, these findings collectively suggest that functions beyond the enzyme activity of cyclin D1 contribute to breast cancer. The novel studies described herein have identified a new region of cyclin D1 that contributes to a malignant biological process called chromosomal instability. Chromosomal instability promotes genetic rearrangements that promote tumorigenesis and create tumor genetic heterogeneity. Unfortunately, many current chemotherapies have the effect of increasing chromosomal instability and thereby tumor genetic heterogeneity. We have identified two different parts of the cyclin D1 molecular that have distinct roles in promoting tumorigenesis: one region that promotes a kinase function and a second distinct region that promotes chromosomal instability. This suggests we may be able to target both the enzyme activity and the separate region that induces chromosomal instability and thereby reduce the appearance of resistant breast cancer cells. Using unique transgenic mice and reconstitution systems, we will define the mechanism by which cyclin D1 induces chromosomal instability. Defining the mechanisms governing cyclin D1-mediated chromosomal instability will allow us to define tailored therapies for breast cancer. The overarching challenge of these studies is to “identify what drives breast cancer growth; determine how to stop it.” These studies will help breast cancer patients who have increased expression of cyclin D1 and/or chromosomal instability (CIN). The potential clinical applications are to combine current therapies with a new class of drugs that inhibit CIN. The potential benefits include improved lifespan for patients or reduced side effects from current therapies. The projected time to achieve a patient-related outcome will be within 3 years as several CIN inhibitors are currently in Phase I/II clinical study. The proposed studies are highly likely to improve survival of patients with breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810605
Entities
People
- Richard Pestell
Organizations
- Baruch S. Blumberg Institute
- United States Army