Protein‑ and growth‑modulatory effects of carcinoma‑associated fibroblasts on breast cancer cells: Role of interleukin‑6.

Carcinoma‑associated fibroblasts (CAFs) secrete factors that increase the expression and/or activities of proteins in breast cancer cells and induce resistance to anti‑estrogens, such as fulvestrant. A major factor is interleukin‑6 (IL‑6). This study demonstrated that, across estrogen receptor (ER)α‑positive and ‑negative cell lines, recombinant human IL‑6 (rhIL‑6) mimicked most of the CAF‑conditioned medium (CM)‑induced changes in protein expression patterns; however, in most cases, it failed to recapitulate CAF‑CM‑triggered alterations in ERK1/2 and AKT activities.

Expression of transmembrane protein 26 (TMEM26) in breast cancer and its association with drug response.

We have previously shown that stromal cells desensitize breast cancer cells to the anti-estrogen fulvestrant and, along with it, downregulate the expression of TMEM26 (transmembrane protein 26). In an effort to study the function and regulation of TMEM26 in breast cancer cells, we found that breast cancer cells express non-glycosylated and N-glycosylated isoforms of the TMEM26 protein and demonstrate that N-glycosylation is important for its retention at the plasma membrane. Fulvestrant induced significant changes in expression and in the N-glycosylation status of TMEM26.

Stromal cells promote anti-estrogen resistance of breast cancer cells through an insulin-like growth factor binding protein 5 (IGFBP5)/B-cell leukemia/lymphoma 3 (Bcl-3) axis.

There is strong evidence that stromal cells promote drug resistance of cancer. Here, we show that mesenchymal stem cells (MSCs) and carcinoma-associated fibroblasts (CAFs) desensitize ERα-positive breast cancer cells to the anti-estrogen fulvestrant. In search for the mechanism, we found that MSCs and CAFs similarly increased the activity of the PI3K/AKT and the JAK/STAT3 pathways and upregulated the expression of integrin β1, IGF1R, HIF1α, CAIX and Bcl-3 in MCF-7 cells.

The impact of tumor stroma on drug response in breast cancer.

In the last two decades the breast cancer mortality rate has steadily declined, in part, due to the availability of better treatment options. However, drug resistance still remains a major challenge. Resistance can be an inherent feature of breast cancer cells, but can also arise from the tumor microenvironment.

Paracrine effects of stem cells in wound healing and cancer progression (Review).

Stem cells play an important role in tissue repair and cancer development. The capacity to self-renew and to differentiate to specialized cells allows tissue-specific stem cells to rebuild damaged tissue and cancer stem cells to initiate and promote cancer. Mesenchymal stem cells, attracted to wounds and cancer, facilitate wound healing and support cancer progression primarily by secreting bioactive factors.

Cyclic AMP enhances TGFβ responses of breast cancer cells by upregulating TGFβ receptor I expression.

Cellular functions are regulated by complex networks of many different signaling pathways. The TGFβ and cAMP pathways are of particular importance in tumor progression. We analyzed the cross-talk between these pathways in breast cancer cells in 2D and 3D cultures.

Mesenchymal stem cells and carcinoma-associated fibroblasts sensitize breast cancer cells in 3D cultures to kinase inhibitors.

Stromal cells, such as mesenchymal stem cells (MSCs) and carcinoma-associated fibroblasts (CAFs), play a role in cancer progression. To analyze their ability to modulate drug response, we generated spheroids of MCF-7 or MDA-MB-231 breast cancer cells in the absence or presence of human (h)MSCs or hCAFs and tested the susceptibility of the breast cancer cells to three different kinase inhibitors (TKI258, RAD001 and RAF265) used in cancer therapy. While stromal cells did not affect the response of either breast cancer cell line to the PDGFR/FGFR/VEGFR inhibitor TKI258, they sensitized breast cancer cells to the mTOR inhibitor RAD001.