Abstract
Simple SummarySmall molecules that inhibit cyclin dependent kinases (CDKs) have great potential for the treatment of breast cancer and have been implemented in the standard of care for some patients with metastatic disease. As the indications for CDK inhibitors continue to expand, and it is crucial to understand the mechanism of action of these drugs and treatment interactions with other targeted therapies. Accordingly, this review discusses subtype-specific systemic breast cancer treatment, the effects of signaling through transforming growth factor beta (TGFβ), and the unique potential for implementation of CDK inhibitor therapy.TGFβ signaling enacts tumor-suppressive functions in normal cells through promotion of several cell regulatory actions including cell-cycle control and apoptosis. Canonical TGFβ signaling proceeds through phosphorylation of the transcription factor, SMAD3, at the C-terminus of the protein. During oncogenic progression, this tumor suppressant phosphorylation of SMAD3 can be inhibited. Overexpression of cyclins D and E, and subsequent hyperactivation of cyclin-dependent kinases 2/4 (CDKs), are often observed in breast cancer, and have been associated with poor prognosis. The noncanonical phosphorylation of SMAD3 by CDKs 2 and 4 leads to the inhibition of tumor-suppressive function of SMAD3. As a result, CDK overactivation drives oncogenic progression, and can be targeted to improve clinical outcomes. This review focuses on breast cancer, and highlights advances in the understanding of CDK-mediated noncanonical SMAD3 phosphorylation. Specifically, the role of aberrant TGFβ signaling in oncogenic progression and treatment response will be examined to illustrate the potential for therapeutic discovery in the context of cyclins/CDKs and SMAD3.
Highlights
Breast cancer is the most common cancer diagnosed among women and the second leading cause of cancer-related death among women in the United States after lung cancer [1]
Our review will focus on the implications of TGFβ signaling and regulation of this pathway using modifications of cell cycle/proliferation checkpoint inhibitors known as cyclin-dependent kinase (CDK) inhibitors, used to treat hormone receptor and human epidermal growth factor receptor 2 (HER2) positive and negative advanced breast cancer
CCNE-high, human growth factor receptor-2 (HER2)+ tumors were sensitive to CDK2/9 inhibition [59,60], supporting the potential for CDK inhibitor therapy to serve as promising modality for the treatment of trastuzumab resistant HER2+ breast cancer
Summary
Breast cancer is the most common cancer diagnosed among women and the second leading cause of cancer-related death among women in the United States after lung cancer [1]. Breast cancers are characterized into major classifications based on signaling receptor expression profile: hormone receptor positive estrogen receptor and/or progesterone receptor (ER and/or PR), human growth factor receptor-2 (HER2) positive, or triple-negative breast cancer (ER/PR/HER2 receptor negative or TNBC) [3] Within these classifications, breast cancer is heterogeneous, underlying the difficulties presented to current therapeutic strategies. In mammary tissue, TGFβ functions as a potent proliferation inhibitor and apoptosis inducer in early stages [12], yet promotes cancer aggressiveness in advanced stages of disease [13,14] This paradoxical dual effect of TGFβ on cancer development and progression supports the investigation of TGFβ canonical and non-canonical pathways to advance the field of breast cancer therapeutics. Our review will focus on the implications of TGFβ signaling and regulation of this pathway using modifications of cell cycle/proliferation checkpoint inhibitors known as cyclin-dependent kinase (CDK) inhibitors, used to treat hormone receptor and human epidermal growth factor receptor 2 (HER2) positive and negative advanced breast cancer
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