Retinoids arrest breast cancer cell proliferation: retinoic acid selectively reduces the duration of receptor tyrosine kinase signaling

Abstract

Retinoic acid (RA) induces cell cycle arrest of hormone-dependent human breast cancer (HBC) cells. Previously, we demonstrated that RA-induced growth arrest of T-47D HBC cells required the activity of the RA-induced protein kinase, protein kinase Cα (PKCα) [J. Cell Physiol. 172 (1997) 306]. Here, we demonstrate that RA treatment of T-47D cells interfered with growth factor signaling to downstream, cytoplasmic and nuclear targets. RA treatment did not inhibit epidermal growth factor (EGF) receptor activation but resulted in rapid inactivation. The lack of sustained EGFR activation was associated with transient rather than sustained association of the EGFR with the Shc adaptor proteins and activation of Erk 1/2 and with compromised induction of expression of immediate early response genes. Inhibiting the activity of PKCα, a retinoic acid-induced target gene, prevented the effects of RA on cell proliferation and EGF signaling. Constitutive expression of PKCα, in the absence of RA, decreased cell proliferation and decreased EGF signaling. RA treatment increased steady-state levels of the protein tyrosine phosphatase PTP-1C and all measured effects of RA on EGF receptor function were reversed by the tyrosine phosphate inhibitor orthovanadate. These results indicate that RA-induced target genes, particularly PKCα, prevent sustained growth factor signaling, uncoupling activated receptor tyrosine kinases and nuclear targets that are required for cell cycle progression.

Protein Kinase C α but not PKCζ Suppresses Intestinal Tumor Formation in ApcMin/+ Mice

“…Early work has shown that cPKCs can themselves phosphorylate EGFR at Thr 654 , thereby decreasing the ligand affinity and signaling capacity of this receptor (63)(64)(65). Additionally, in a recent report, PKCa has been shown to phosphorylate protein tyrosine phosphatase PTP-1C, which in turn deactivates EGFR and decreases ERK phosphorylation in response to retinoid treatment in breast cancer cells (66). Taken together, these data support our notion that EGFR signaling is altered in the PKCa-deficient intestine.…”

Upregulation of retinoic acid receptor‐β by the epidermal growth factor‐receptor inhibitor PD153035 is not mediated by blockade of ErbB pathways

“…We and others have shown that ErbB and retinoid signaling systems interact with each other at multiple molecular and cellular levels (Grunt et al, 1998; Offterdinger et al, 1998, 1999, 2003; Schneider et al, 1999; Grunt, 2003; Tighe and Talmage, 2004). Preliminary data suggested that PD153035 elevates the expression of RAR‐β (Grunt et al, 2005).…”

“…We and others have previously shown that ErbB and retinoid pathways interact at several molecular and cellular levels with each other. For instance, retinoids downregulate the expression of ErbB receptors (Grunt et al, 1998; Offterdinger et al, 1998, 1999; Schneider et al, 1999) in breast and ovarian cancer and prematurely silence EGF signaling (Tighe and Talmage, 2004). Experimental evidence also indicates that heregulin—a ligand that binds ErbB‐3 or ‐4 and indirectly activates EGFR and ErbB‐2—cooperates with retinoids during stimulated in vitro differentiation of mammary carcinoma cells (Offterdinger et al, 2003).…”

CRABP1 is associated with a poor prognosis in breast cancer: adding to the complexity of breast cancer cell response to retinoic acid

“…RA and its derivatives, collectively called retinoids, inhibit growth and induce apoptosis in a variety of epithelial cancer cells and hold great promise as chemotherapeutic agents [ 7 – 9 ]. Retinoids inhibit mitogen signalling [ 10 ] and induce downstream signalling pathways implicated in growth arrest, apoptosis and differentiation of precancerous and cancer cells [ 11 – 15 ]. However, with the exception of acute promyelocytic leukemia (APL) [ 14 , 16 , 17 ], clinical trials designed to test the efficacy of RA and its derivatives in the treatment of cancer have produced disappointing results, primarily because of RA-induced side effects and development of RA resistance [ 18 , 19 ].…”