Persistent Activation of NF-κB in BRCA1-Deficient Mammary Progenitors Drives Aberrant Proliferation and Accumulation of DNA Damage

Abstract

Human BRCA1 mutation carriers and BRCA1-deficient mouse mammary glands contain an abnormal population of mammary luminal progenitors that can form 3D colonies in a hormone-independent manner. The intrinsic cellular regulatory defect in these presumptive breast cancer precursors is not known. We have discovered that nuclear factor kappaB (NF-κB) (p52/RelB) is persistently activated in a subset of BRCA1-deficient mammary luminal progenitors. Hormone-independent luminal progenitor colony formation required NF-κB, ataxia telangiectasia-mutated (ATM), and the inhibitor of kappaB kinase, IKKα. Progesterone (P4)-stimulated proliferation resulted in a marked enhancement of DNA damage foci in Brca1(-/-) mouse mammary. In vivo, NF-κB inhibition prevented recovery of Brca1(-/-) hormone-independent colony-forming cells. The majority of human BRCA1(mut/+) mammary glands showed marked lobular expression of nuclear NF-κB. We conclude that the aberrant proliferative capacity of Brca1(-/-) luminal progenitor cells is linked to the replication-associated DNA damage response, where proliferation of mammary progenitors is perpetuated by damage-induced, autologous NF-κB signaling.

Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer

“…Linking BRCA1’s roles in proper mammary cell differentiation and DSB repair, recent studies have shed light on why luminal progenitor cells may be more sensitive to defects in BRCA1’s DSB repair function (Nolan et al 2016, Sau et al 2016). Luminal progenitors in preneoplastic breast tissue from BRCA1 mutation carriers separate into two distinct populations, RANK+ and RANK−, based on expression of the receptor for RANK ligand, a paracrine effector of progesterone signaling.…”

“…Combined with the observation that the RANK+ cells have a molecular signature more similar to basal-like breast cancer than any other subtype, these findings suggest that the RANK+ luminal progenitor cells may represent the cell-of-origin population for the basal-like breast cancers arising in BRCA1 mutation carriers and that RANK ligand (RANKL) may be a valuable therapeutic target in these patients (Nolan et al 2016). Similarly, the NF-κB pathway is persistently activated in a subset of luminal progenitor cells from preneoplastic BRCA1 mut /+ breast tissue (Sau et al 2016). Sau et al (2016) found that progesterone-stimulated proliferation increases NF-κB signaling and the accumulation of DNA damage.…”

“…Similarly, the NF-κB pathway is persistently activated in a subset of luminal progenitor cells from preneoplastic BRCA1 mut /+ breast tissue (Sau et al 2016). Sau et al (2016) found that progesterone-stimulated proliferation increases NF-κB signaling and the accumulation of DNA damage. Thus, it has been hypothesized that overly active progesterone-induced signaling via the NF-κB pathway and paracrine mediator RANKL may account for the tissue specificity and cell of origin for BRCA1-associated breast cancers.…”

RANKL/RANK: from bone loss to the prevention of breast cancer

“…Furthermore, these authors also found a significant RANKL-dependent reduction of tumour incidence in a mouse model of transplanted mammary tumours [71]. Moreover, in another study, nuclear factor kappaB (NFκB), a well-known downstream target of RANK, was shown to be persistently activated by DNA damage in BRCA1 -deficient mammary progenitors and in vivo inhibition of NFκB prevented hormone-independent colony formation of luminal progenitor cells [72]. Figure 4 depicts the current understanding of RANKL/RANKL function in BRCA1 -mutated breast cancer.…”

Pharmacological Dual Inhibition of Tumor and Tumor-Induced Functional Limitations in a Transgenic Model of Breast Cancer

“…Genome-wide comparative analyses of multiple transgenic mammary tumor models have suggested PyMT + model to represent the luminal B intrinsic subtype of breast cancer (21). We used dimethylaminoparthenolide (DMAPT), a water-soluble analogue of parthenolide, which we have previously shown to have potent NF-κB inhibitory activity (22) and has been shown to overcome the adverse effects of persistent activation of NF-κB in BRCA1-deficient mammary luminal progenitor cells in vivo (23). We found that mammary tumor development in PyMT + mice was accompanied with functional limitations such as reduced grip strength, impaired rotarod balance, causing altered body composition as well as molecular changes in muscle including reduced expression of miR-486 and MyoD as we reported previously (14).…”