Mammary gland growth factors: roles in normal development and in cancer

Abstract

Normal development of the mammary gland proceeds via interactions between the epithelium and the mesenchyme that start during embryogenesis and continue during pubertal outgrowth and differentiation. The function of specific peptide growth factors that bind members of the receptor tyrosine kinase family and the cytokine receptor family are required at each stage. In many cases the peptides are produced in one compartment and act on receptors in the other compartment. One of the striking differences between normal development and cancer is the loss of this cross-talk. Mammary tumor cells often produce a peptide and express the receptor on the same cell leading to autocrine activation of signaling pathways, a mechanism that is characteristic for cancer cells. We will discuss different peptides in the context of normal development and cancer in this review.

Figure 1.

EGF-family peptides and ErbB Receptors. The four ErbB receptors are shown: (1) EGFR, (2) ErbB2, (3) ErbB3, and (4) ErbB4. The EGF-family peptides bind specific ErbB receptors: EGF, TGF-α,AR, and EPG bind EGFR; BTC, HB-EGF, EPR have dual specificity, binding both EGFR and ErbB4; NRG-1 and NRG-2 bind ErbB3 and ErbB4; NRG-3 and NRG-4 bind ErbB4 (Hynes and Lane 2005). Various roles for specific ligands (boxed in red) and all the ErbB receptors have been described in normal mammary gland development. In breast cancer, overexpressed ErbB2 together with ErbB3 function as a unit to drive proliferation of specific subsets of tumors (Holbro et al. 2003). EGFR is overexpressed in 30%–60% of basal-like breast cancers. See text for more information.

Figure 2.

Members of the FGF family are divided into six subgroups of closely related peptides. Each ligand binds to a specific subset of the FGFRs. () refers to the fact that there is still uncertainty regarding the binding. The table summarizes results from many laboratories and some relevant publications are as follows: (Ornitz et al. 1996; Zhang et al. 2006; Kurosu et al. 2006, 2007; Suzuki et al. 2008; Schwertfeger 2009).

Figure 3.

Deregulation of FGF ligands and receptors in mammary cancer. MMTV proviral insertional mutagenesis led to the identification of five FGF ligands and the FGFR2 whose expression promoted mammary cancer. Some of these ligands have also been implicated in human breast cancer. FGFR1 and FGFR2 have also been shown to contribute to breast cancer development, whereas FGFR4 has been implicated in therapy response. The references used for this figure are: (1) (Theodorou et al. 2007), (2) (Peters et al. 1989), (3) (Theodorou et al. 2004), (4) (MacArthur et al. 1995), (5) (Naidu et al. 2001), (6) (Fioravanti et al. 1997), (7) (Berns et al. 1995), (8) (Jacquemier et al. 1998), (9) (Bansal et al. 1997), (10) (Zammit et al. 2002), (11) (Marsh et al. 1999), (12) (Adnane et al. 1991), (13) (Ray et al. 2004), (14) (Reis-Filho et al. 2006), (15) (Hunter et al. 2007), (16) (Easton et al. 2007), (17) (Meijer et al. 2008), (18) (Bange et al. 2002).

Figure 4.

Cytokine signaling through the Jak/Stat pathway in mammary gland development. Sequential activation of Stat6 and Stat5 control alveologenesis during pregnancy. These Stats are activated in response to specific ligands, IL-4 and IL-13 (Stat6) and Prl (Stat5) that bind to receptors of the cytokine family. During involution, cell death is mediated by Stat3, which is activated by LIF and then by OSM, which share the common gp130 receptor. Stat signaling is negatively regulated by the family of SOCS proteins that are direct transcriptional targets of each Stat factor. Once activated, Stats bind to similar consensus sequences but activate transcription of distinct sets of target genes to control mammary gland development.

Figure 5.

Constitutive Stat3 activity in tumors affects the surrounding microenvironment. Chronic Stat3 activation in tumor cells results in secretion of IL-1β, IL-6, and IL-10; these in turn act on nontumor cells, T helper 17 cells (Th17) and tumor associated macrophages (TAM) resulting in further secretion of cytokines, which act in a feedback loop to promote growth and differentiation of the tumor cells. Stat3-directed secretion of IL-10 by the tumor cells also results in inhibition of antitumor immunity, for example by inhibiting the maturation of dendritic cells (DCs). Thus, Stat3 and the cytokines that it induces, promote tumor invasion and metastasis. Diagram adapted from Pensa et al. (2009).