Paracrine signaling in mammary gland development: what can we learn about intratumoral heterogeneity?

Abstract

Paracrine signaling mechanisms play a critical role in both normal mammary gland development and breast cancer. Dissection of these mechanisms using genetically engineered mouse models has provided significant insight into our understanding of the mechanisms that guide intratumoral heterogeneity. In the following perspective, we briefly review some of the emerging concepts in this field and emphasize why elucidation of these pathways will be important for future progress in devising new and improved combinatorial therapeutic approaches for breast and other solid cancers.

Figure 1

Signaling interactions in mammary development and cancer. (A) An abbreviated view of paracrine interactions in mammary development. Estrogen receptor alpha/progesterone receptor-positive (ERα/PR⁺) cells provide extrinsic cues to ERα/PR^- cells to enable proliferation. Hormone-specific paracrine mediators involve amphiregulin, which acts downstream of estrogen, and RANKL (receptor activator of nuclear factor kappa-B ligand) and Wnt4, which act downstream of progesterone signaling. Other known paracrine mediators involve Wnts, fibroblast growth factors (FGFs), insulin-like growth factor, bone morphogenetic proteins, transforming growth factor-beta (TGF-β), and Notch; however, owing to space limitations, not all are depicted in this simple model. (B) Breast cancer subtypes reveal both inter- and intratumoral heterogeneity. Studies have identified interactions between ERα⁺ cancer cells and ERα^- cancer cells involving epidermal growth factor, FGF, and Notch interactions. The identification of signaling crosstalk between cancer cell subpopulations within breast cancer subtypes remains a challenge, yet certain pathways have been identified, including PR/RANKL, Wnt, Notch, and TGF-β. Further studies are required to elucidate the details of subtype-specific differences in paracrine signaling pathways. Cells of the microenvironment (not depicted in this graphic) provide another layer of complexity and play an instrumental role in tumor progression and heterogeneity. EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; MaSC, mammary stem cell; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cell.