A precision approach to breast cancer treatment based on cell lineage-specific vulnerabilities.

Abstract

Breast cancers display significant intra-tumoral heterogeneity posing a major barrier to effective breast cancer treatments [1, 2]. This heterogeneity can be manifested in terms of genetic abnormalities or the presence of distinct cell types bearing similarities to the different epithelial lineages in the normal adult mammary gland including: luminal cells, basal cells, their respective progenitors, and stem cells [3]. The cell lineages present within a given tumor may determine the likelihood of progression. This is best exemplified by sub-populations of tumor-initiating cells present in aggressive breast cancers, some of which resemble adult mammary stem cells [4-9] and thus are termed stem-like. These stem-like cells are enriched in residual tumors after chemotherapy [10] as well as early metastatic lesions [11], suggesting they play a critical role in breast cancer progression. While attempts to treat breast cancers based on genetic mutations have largely been unsuccessful, therapies targeting particular cell lineages, including stem-like cells, are gaining renewed appreciation. Toward this goal, studies have uncovered distinct dependencies among different breast cancer cell types for particular cell death/survival pathways. These recent advances may open the door for new highly personalized approaches to breast cancer therapy. Our previous studies found that stem-like cells were highly sensitive to cell death induced by p53-upregulated mediator of apoptosis (PUMA) [12], a pro-apoptotic BH3-only member of the Bcl-2 family. These effects were specific to PUMA [12] as the related family member NOXA had no effect on stem-like cells consistent with its role in targeting basal-like breast cancer cells [13]. We further found that driving PUMA expression was sufficient to deplete stem-like cells and reduce metastasis in vivo, revealing its role as an important metastasis suppressor. Our results are consistent with published findings that PUMA-mediated cell death is the preferred response in some normal adult stem cell populations [14]. In an effort Research Perspective