Targeting Basal Breast Cancer
Abstract
The National Cancer Institute estimates that the incidence of breast cancer will double by 2030. Reproductive history is a major risk factor for breast cancer. This suggests that changes in breast during development and with each cycle of ovulation and pregnancy increase susceptibility to breast cancer. It is therefore imperative to understand links between these natural processes and tumor initiation at a cellular and molecular level. Amplification of breast stem cells is a likely predisposing determinant of breast cancer initiation risk and susceptibility. Under normal circumstances, breast stem cells undergo phases of dormancy and activation. During normal development, fetal mammary stem cells multiply and invade to form a small tree under the skin. A few cells at the tip of each branch later function as pubertal mammary stem cells to extend the ductal tree during adolescence. A small number of cells, scattered along the branches, continue to serve as adult mammary stem cells to generate milk-producing structures during pregnancy. These structures are removed at the end of breastfeeding and regenerated with every pregnancy. Dormancy and activation of mammary stem cells is tightly controlled by signals from surrounding cells. In breast and several other tissues, Wnt signals activate normal stem cells. The stem cells in many human breast tumors divide uncontrollably due to loss of factors in their surroundings that would naturally oppose Wnt signals (e.g., sFRP). There is an unmet need for markers that reliably identify breast stem cells and long-lived progenitors. Such markers could have significant value in (i) distinguishing deadly from indolent forms of breast cancer, (ii) monitoring for aberrant stem cell dynamics during stages of the reproductive cycle associated with heightened risk of breast cancer initiation, and (iii) eradicating breast tumor cells that generate tumors and lead to recurrence after treatment. We have identified a protein, Gpr, that holds promise as a highly specific marker of normal breast stem cells. Our preliminary data show high levels of Gpr in human basal breast cancer. Moreover, higher levels are associated with a particularly poor outcome within this subtype. Little is understood about the etiology of basal breast cancer. Thirty percent of patients with basal breast cancers succumb within 3 years, and new markers are needed to identify these patients and distinguish them from the remaining seventy percent. We aim to validate Gpr as a novel marker with potential to distinguish deadly from indolent cancers. We have devised a genetic mouse model that allows us to identify, isolate, and kill cells that express Gpr. Gpr+ cells are massively expanded and associated with accelerated tumor onset in mouse models of human basal breast cancer. We will test whether Gpr marks normal breast stem cells and cancer stem cells that generate basaloid tumors in mice. These mice offer an opportunity to elucidate the role of normal mammary stem cells in breast cancer initiation, risk, and susceptibility. We will test whether eradicating Gpr+ cells will halt and prevent tumor formation in mice. This work promises to define a marker to detect, track, and eradicate the cellular source of tumor recurrence in a subset of basal breast cancer. In the longer term, a reliable identifier of breast stem cells promises to shift breast cancer management towards prevention by enabling abnormal stem cell activity to be monitored during stages in the reproductive cycle associated with heightened breast cancer risk.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1710013
Entities
People
- Pamela Cowin
Organizations
- Grossman School of Medicine
- United States Army