Cytokine sensitivity screening highlights BMP4 pathway signaling as a therapeutic opportunity in ER ⁺ breast cancer

Abstract

Despite the success of approved systemic therapies for estrogen receptor (ER)α-positive breast cancer, drug resistance remains common. We hypothesized that secreted factors from the human tumor microenvironment could modulate drug resistance. We previously screened a library of 297 recombinant-secreted microenvironmental proteins for the ability to confer resistance to the anti-estrogen fulvestrant in 2 ER breast cancer cell lines. Herein, we considered whether factors that enhanced drug sensitivity could be repurposed as therapeutics and provide leads for drug development. Screening data revealed bone morphogenic protein (BMP)4 as a factor that inhibited cell growth and synergized with approved anti-estrogens and cyclin-dependent kinase 4/6 inhibitors (CDK4/6). BMP4-mediated growth inhibition was dependent on type I receptor activin receptor-like kinase (ALK)3-dependent phosphorylation (P) of mothers against decapentaplegic homolog (SMAD/P-SMAD)1 and 5, which could be reversed by BMP receptor inhibitors and ALK3 knockdown. The primary effect of BMP4 on cell fate was cell-cycle arrest, in which RNA sequencing, immunoblot analysis, and RNA interference revealed to be dependent on p21 upregulation. BMP4 also enhanced sensitivity to approved inhibitors of mammalian target of rapamycin complex 1 and CDK4/6 via ALK3-mediated P-SMAD1/5 and p21 upregulation in anti-estrogen-resistant cells. Patients bearing primary ER breast tumors, exhibiting a transcriptomic signature of BMP4 signaling, had improved disease outcome following adjuvant treatment with anti-estrogen therapy, independently of age, tumor grade, and tumor stage. Furthermore, a transcriptomic signature of BMP4 signaling was predictive of an improved biologic response to the CDK4/6 palbociclib, in combination with an aromatase inhibitor in primary tumors. These findings highlight BMP4 and its downstream pathway activation as a therapeutic opportunity in ER breast cancer.-Shee, K., Jiang, A., Varn, F. S., Liu, S., Traphagen, N. A., Owens, P., Ma, C. X., Hoog, J., Cheng, C., Golub, T. R., Straussman, R., Miller, T. W. Cytokine sensitivity screening highlights BMP4 pathway signaling as a therapeutic opportunity in ER breast cancer.

Integrated pan-cancer gene expression and drug sensitivity analysis reveals SLFN11 mRNA as a solid tumor biomarker predictive of sensitivity to DNA-damaging chemotherapy

“…Components of the TME including stromal cells and secreted factors have been implicated in drug resistance to both chemotherapeutics and targeted agents in a multitude of cancer types [20, 21]. Similarly, TME components such as secreted factors, hypoxia and acidity have been shown to contribute to enhancing drug sensitivity in cancer [40–42]. Determining potential interplay between SLFN11 expression, the tumor microenvironment, and sensitization to chemotherapy represents a logical and clinically important next step.…”

Cyclin-Dependent Kinases 4/6 Inhibitors in Breast Cancer: Current Status, Resistance, and Combination Strategies

“…And screening data showed that bone morphogenetic protein (BMP) 4 could inhibit cell growth and synergize with endocrine therapy and CDK4/6 inhibitors. By upregulation of p21, BMP4 enhanced sensitivity to CDK4/6 inhibitors in estrogen-resistant cells (Figure 2) 86. Furthermore, transcriptomic features of BMP4 signaling predicted an improved biological response to the palbociclib combined with an aromatase inhibitor 86.…”

“…By upregulation of p21, BMP4 enhanced sensitivity to CDK4/6 inhibitors in estrogen-resistant cells (Figure 2) 86. Furthermore, transcriptomic features of BMP4 signaling predicted an improved biological response to the palbociclib combined with an aromatase inhibitor 86. Fangchinoline is an alkaloid with cytotoxic, anti-inflammatory and antioxidant properties.…”

High expression of bone morphogenetic protein (BMP) 6 and BMP7 are associated with higher immune cell infiltration and better survival in estrogen receptor‑positive breast cancer

“…It is well known that certain signaling, such as HER2, crosstalks with ER signaling and the targeted drug sensitivity is enhanced by ER blockade (30). Signaling of BMPs is also known to crosstalk with that of ER (31,32). Therefore, it was of interest to investigate the association of ER positivity and BMP expression.…”