Mammary Development and Breast Cancer: a Notch Perspective

Abstract

Mammary gland development primarily occurs postnatally, and this unique process is complex and regulated by systemic hormones and local growth factors. The mammary gland is also a highly dynamic organ that undergoes profound changes at puberty and during the reproductive cycle. These changes are driven by mammary stem cells (MaSCs). Breast cancer is one of the most common causes of cancer-related death in women. Cancer stem cells (CSCs) play prominent roles in tumor initiation, drug resistance, tumor recurrence, and metastasis. The highly conserved Notch signaling pathway functions as a key regulator of the niche mediating mammary organogenesis and breast neoplasia. In this review, we discuss mechanisms by which Notch contributes to breast carcinoma pathology and suggest potentials for therapeutic targeting of Notch in breast cancer. In summary, we provide a comprehensive overview of Notch functions in regulating MaSCs, mammary development, and breast cancer.

Keywords: Breast cancer; Mammary development; Notch signaling; Stem cell.

Fig. 1

Diagram of postnatal mammary gland development. Mammary gland development involves four major stages: embryonic, pubertal, adult and reproductive. According to previous reports, Notch1 regulates epithelial cell differentiation during embryonic development. DLL1, Notch3 and Numb/NumbL affect mammary duct elongation and side branch formation at puberty. Besides, Notch3 regulates the formation of duct side branches at adult stages. During pregnancy, Notch1-4 could regulate alveolar cells formation and milk production. In addition, Elf5 could function during pregnancy via Notch signaling

Fig. 2

Canonical Notch signaling cascades in mammals. Notch ligands bind to the extracellular domain (NECD) of their receptor proteins, inducing receptor transactivation to expose the receptor transmembrane domain for ADAM/TACE metalloenzyme-mediated hydrolysis. NECD is pulled from the intracellular domain (NICD), and the NICD is cleaved by γ-secretase at an intracellular position to produce the free NICD fragment. The NICD is translocated from the cytoplasm to the nucleus, where it binds with CSL (CBF1/RBP-J/Su(H)/Lag-1) transcription factors to recruit a coactivator (MAML) and form a transcription complex that can activate the transcription of downstream genes (HEY, HES, HERP, CyclinD1, c-Myc, and others)

Fig. 3

Model of the canonical Notch signaling pathway in mouse and human mammary gland epithelial cell development. The Notch pathway has dual functions in mammary gland epithelial cells. In basal cells, DLL1 and Notch1 are necessary to maintain the activity and self-renewal ability of MaSCs, and inhibition of Notch signaling leads to abnormal MaSCs expansion. In addition, Notch2/3/4 and Cbf1 could promote luminal progenitor cell differentiation towards the luminal cell lineage

Fig. 4

The cartoon schematically depicts the involvement of Notch pathway components in breast carcinogenesis