The Tumor Microenvironment as a Regulator of Endocrine Resistance in Breast Cancer

Abstract

Estrogen receptor positive breast neoplasias represent over 70% of diagnosed breast cancers. Depending on the stage at which the tumor is detected, HER2 status and genomic risk, endocrine therapy is combined with either radio, chemo and/or targeted therapy. A growing amount of evidence supports the notion that components of the tumor microenvironment play specific roles in response to treatment and that strategies targeting these key interactions with tumor cells could pave the way to a new generation of therapies. In this review, we analyze the evidence suggesting different components of the tumor microenvironment play a role in hormone receptor positive breast cancer progression. In particular we focus on the immune system, carcinoma associated fibroblasts and the extracellular matrix. Further insight into the cross talk between these constituents of the microenvironment and the tumor cells may lead to therapies that eliminate disseminated metastatic cells early on, and thus reduce distant disease relapse which is the leading cause of death for patients who are diagnosed with this illness.

Keywords: breast cancer; carcinoma associated fibroblasts; endocrine resistance; estrogen receptor; extracellular matrix; immune system; microenvironment.

Figure 1

ERα structume. The functional domains ERα include the DNA binding domain (DBD), ligand binding domain (LBD), and two transcriptional activation functions (AF), the AF-1 ligand-independent activation function domain and the AF-2 ligand-dependent activation domain. The A/B domain, at the amino terminus of the protein, contains AF-1. The C domain binds to DNA motifs (EREs) at target genes. The D domain or hinge region contributes to DNA binding specificity and nuclear localization. The E domain or LBD interacts with estrogens or SERMs. At the C- terminus is the F domain.

Figure 2

Immune system and ER+ breast tumors. Tumor associated macrophages protect cancer cells from the anti-tumor immune responses. M2 macrophages are increased in tumors in comparison to healthy controls and patients with benign lesions. CD204 expression in tumor associated macrophages is enhanced in patients with invasive breast cancer. Macrophages isolated from mouse and human tumors can directly suppress T cell responses in vitro, which are recognizable by the expression of CD8. Response to anti PD-1/PD-L1 monotherapy in metastatic ER+ breast cancer showed durable clinical benefit in a low percentage of patients, although very few studies have addressed this issue.

Figure 3

Carcinoma associated fibroblasts. Two CAF populations were identified through differential expression of CD146 in human breast tumors. CD146 is a stromal surface marker that defines fibroblast subtypes in the hematopoietic stem cell niche. In the context of breast cancer, CD146⁻ CAFs were shown to suppress ERα expression in MCF-7 cells, decreased sensitivity to estrogen, and increase resistance to tamoxifen. On the other hand, the presence of CD146⁺ CAFs promoted ERα expression and sustained estrogen-dependent proliferation and sensitivity to tamoxifen. PDGF receptors and ligands have recently been shown to actually modulate whether a tumor is luminal or basal and thus whether it may or not respond to endocrine therapy [Permission obtained from Springer Nature (73)].

Figure 4

The extracellular matrix. FN is associated to disease progression in breast cancer. Culturing ERα+ human breast cancer cells on FN leads to endocrine resistance through binding to β1 integrin. When cells are in contact with FN, ERα is not downregulated after 1 h treatment with estradiol. Estradiol induces endocytosis in breast cancer cells and ERα located at the cell membrane travels in endosomes to the nucleus. When FN is present, ERα is endocytosed and “dragged” by β1 integrin back to the cell surface, apart from going to the nucleus. Also, there is no co-localization of ERα with the lysosomal compartment strongly supporting the notion that the β1 integrin/FN interaction directs the fate of ERα and thus response to tamoxifen.