Integrins and Actions of Androgen in Breast Cancer

Abstract

Androgen has been shown to regulate male physiological activities and cancer proliferation. It is used to antagonize estrogen-induced proliferative effects in breast cancer cells. However, evidence indicates that androgen can stimulate cancer cell growth in estrogen receptor (ER)-positive and ER-negative breast cancer cells via different types of receptors and different mechanisms. Androgen-induced cancer growth and metastasis link with different types of integrins. Integrin αvβ3 is predominantly expressed and activated in cancer cells and rapidly dividing endothelial cells. Programmed death-ligand 1 (PD-L1) also plays a vital role in cancer growth. The part of integrins in action with androgen in cancer cells is not fully mechanically understood. To clarify the interactions between androgen and integrin αvβ3, we carried out molecular modeling to explain the potential interactions of androgen with integrin αvβ3. The androgen-regulated mechanisms on PD-L1 and its effects were also addressed.

Keywords: PD-L; androgen; androgen receptor; breast cancer; integrin αvβ3.

Figure 1

Schematically representing the signal transduction and biological activities induced by androgen in ER-positive breast cancer cells. Endogenous androgen, DHT, activates ER-mediated PI3K/Akt and ERK1/2 signaling pathways to regulate cell proliferation. Moreover, the process of ERK1/2-mediated cell proliferation is controlled by the activation of EGFRs stimulated by EGF, as well as the activation of iAR induced by the synthetic androgen, R1881. Upon EGFRs activation, it not only involves the formation of an association between iAR and Src complex but also triggers cell proliferation through PI3K/Akt/ERK1/2 signaling. Stimulation of mAR by TAC triggers the phosphorylation of FAK and Akt, resulting in enhanced cell apoptosis. In this mAR-mediated apoptosis, SGK1 plays a role in improving the apoptotic effect. Cell motility is downregulated upon mAR activation through the FAK/PI3K/Rac1 signaling pathway. In the absence of AR-driven signaling, EGFR induces PKC-mediated ERK1/2 activation and PN-1 expression to suppress cell motility. ERβ also inhibits cell motility through induction of integrin α1β1. The red arrows indicate Erβ/ integrin α1β1 pathway; The purple arrows indicate EGF/EGFR/PKC/ERK1/2/PN-1 pathway.

Figure 2

Schematically representing the signal transduction and biological activities induced by androgen in ER-negative breast cancer cells. Activation of iAR by DHT stimulates ERK1/2-mediated cell proliferation either directly or through cross-talk with EGFRs. Additionally, DHT binding to integrin αvβ3 activates the FAK/ERK1/2 signaling pathway, resulting in phosphorylated ERK1/2 translocation to the nucleus and subsequent cell proliferation. The association of iAR, PI3K, and Src induced by R1881 leads to cell motility through the FAK/Akt/paxillin signaling pathway. The function of mAR activated by TAC is similar to that in ER-positive breast cancer cells. Without AR-driven signaling, EGFR enhances cell motility and proliferation by triggered Rac1/PI3K/Akt/PAK1 signaling and Src/ERK1/2 signaling, respectively. Integrin α3β1 or β1 can direct activate PI3K/Akt signaling to regulate cell motility. After binding of TGF-βR with TGF-β, integrin αv phosphorylates Smad2/3 to increase cell motility. The red arrows indicate integrin α3β1/PI3K/Akt/BRN2 pathway; The blue arrows indicate EGF/EGFR/Src/ERK1/2 pathway.

Figure 3

Diagram illustrating the androgen-mediated signal transduction via integrins and the resulting biological activities. (A) Integrin-induced cell motility and adhesion are mediated by AR. Activation of iAR by DHT or R1881 affects different subtypes of integrin expression to regulate cell adhesion and motility. RANK/RANKL promotes iAR expression through integrin α2β1 and induces integrin α2β1-involved cell adhesion via FAK/Akt signaling pathway. In AR-expressing cells, FAK signaling modulates integrin α5β1-induced cell adhesion and integrin αv-induced cell motility. (B) Integrin-induced cell growth and survival are mediated by AR. Activation of iAR by R1881 induces the expression of integrin α6β1, which in turn regulates cell survival through HIF-1α-promoted BNIP3 expression. Furthermore, iAR activity is up-regulated by integrin αvβ6, leading to increased survivin expression and enhanced cell growth. The activation of IGF-IR suppresses the degradation of integrin α5β1 through endocytosis, allowing this remaining integrin α5β1 to induce cell growth. The brown arrows indicate RANK/integrin α2β1/ transcription factor (TF)/iAR and RANK/integrin α2β1/FAK/Akt pathways; The dark blue arrows indicate integrin α5β1/FAK/Akt pathway; The purple arrows indicate integrin αv/FAK/mTOR pathway; The light blue arrows indicate IGF-1R/ integrin α5β1 pathway; The red arrows indicate R1881/iAR/integrin α6β1 pathway; The green arrows indicate integrin αvβ6/JNK/iAR (activity)/survivin pathway; The orange arrows indicate integrin α6β1/HIF-1α/BNIP3 pathway.

Figure 3

Diagram illustrating the androgen-mediated signal transduction via integrins and the resulting biological activities. (A) Integrin-induced cell motility and adhesion are mediated by AR. Activation of iAR by DHT or R1881 affects different subtypes of integrin expression to regulate cell adhesion and motility. RANK/RANKL promotes iAR expression through integrin α2β1 and induces integrin α2β1-involved cell adhesion via FAK/Akt signaling pathway. In AR-expressing cells, FAK signaling modulates integrin α5β1-induced cell adhesion and integrin αv-induced cell motility. (B) Integrin-induced cell growth and survival are mediated by AR. Activation of iAR by R1881 induces the expression of integrin α6β1, which in turn regulates cell survival through HIF-1α-promoted BNIP3 expression. Furthermore, iAR activity is up-regulated by integrin αvβ6, leading to increased survivin expression and enhanced cell growth. The activation of IGF-IR suppresses the degradation of integrin α5β1 through endocytosis, allowing this remaining integrin α5β1 to induce cell growth. The brown arrows indicate RANK/integrin α2β1/ transcription factor (TF)/iAR and RANK/integrin α2β1/FAK/Akt pathways; The dark blue arrows indicate integrin α5β1/FAK/Akt pathway; The purple arrows indicate integrin αv/FAK/mTOR pathway; The light blue arrows indicate IGF-1R/ integrin α5β1 pathway; The red arrows indicate R1881/iAR/integrin α6β1 pathway; The green arrows indicate integrin αvβ6/JNK/iAR (activity)/survivin pathway; The orange arrows indicate integrin α6β1/HIF-1α/BNIP3 pathway.

Figure 4

Predicted docking poses of DHT bound at the cRGD−binding site of integrin αvβ3. The generation of docking poses and further scoring were done by AutoDock 4 and PyMOL, as previously described [99]. (A) The two−dimensional structure of DHT. (B) Close−up of DHT binding mode, superimposed with cRGD peptide within the integrin αvβ3. (C,D) The amino acid residues of integrin αvβ3 interact with the DHT molecule.