Approaches used to treat breast cancer include hormonal, cytotoxic, and targeted therapeutic agents. At present, breast cancer represents one of the few cancers wherein treatment options are based on molecular targets. Notably, estrogen receptor (ER) status is a critical determinant for therapy administration, wherein ER-positive tumors are treated with antagonists of ER function (e.g. tamoxifen) or through ER ligand depletion strategies (e.g. aromatase inhibitors). However, a large percentage of ER-positive tumors ultimately fail such hormone therapies, indicating that parameters independent of ER status have a major impact on therapeutic response. Conversely, for ER-negative breast cancers, there are relatively few indicators of response to cytotoxic therapies. Thus, delineating key determinants of therapeutic efficacy and identifying alternative therapeutic strategies is of high importance. Preliminary data demonstrate that the retinoblastoma tumor suppressor, RB, is a critical determinant of the response to hormone therapy. Specifically, RB-deficient breast tumors fail to effectively respond to estrogen ablation and tamoxifen treatment, as monitored in preclinical models. Additional studies revealed that the gene expression """"""""signature"""""""" of RB loss is strongly associated with early relapse in breast cancer patients treated with tamoxifen. Importantly, elements of this same signature are observed in a number of the predictive signatures that were explicitly developed to define risk of failure with tamoxifen and similar therapeutic regimens. Thus, these combined data indicate that RB-pathway function is requisite for efficacy of the response to endocrine based therapeutic agents. Importantly, such tumors that fail endocrine therapies, including both ER-positive and ER-negative disease, are treated with cytotoxic agents. In this context, we have found that RB loss sensitizes breast cancer cells to specific cytotoxic agents. Conversely, in those tumors that harbor endogenous RB, pharmacological activation of tumor suppressor activity elicits potent activity in multiple sub-types of breast cancer. Based on these findings, we hypothesize that RB is a critical determinant of therapeutic response in breast cancer upon which interventions can be directed. This hypothesis will be interrogated in three aims that will: Define the mechanisms through which RB-mediated transcription controls the response to endocrine therapy;Determine the impact of RB activity on therapy resistant breast cancer;Delineate the action of RB loss on cytotoxic interventions in breast cancer: Combined, these analyses will define the mechanisms through which the RB pathway contributes to alterations in therapeutic response in breast cancer and will elucidate new avenues to direct therapeutic intervention rationally in this tumor type.
Narrative: Breast cancer is a leading cause of female cancer death in this country, indicating a key need for more effective intervention. Here we will explore the role of the RB tumor suppressor that is lost in breast cancer in controlling the response to therapy. Combined, these analyses will define the mechanisms through which the RB contributes to therapeutic response in breast cancer, elucidate new avenues to direct therapeutic intervention rationally in breast cancer, and provide additional targets for breast cancer treatment.
|Knudsen, Erik S; Witkiewicz, Agnieszka K (2017) The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies. Trends Cancer 3:39-55|
|Knudsen, Erik S; Witkiewicz, Agnieszka K (2016) Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2- breast cancer. Oncotarget 7:69111-69123|
|Knudsen, Erik S; McClendon, A Kathleen; Franco, Jorge et al. (2015) RB loss contributes to aggressive tumor phenotypes in MYC-driven triple negative breast cancer. Cell Cycle 14:109-22|
|Asghar, Uzma; Witkiewicz, Agnieszka K; Turner, Nicholas C et al. (2015) The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 14:130-46|
|Witkiewicz, A K; Cox, D W; Rivadeneira, D et al. (2014) The retinoblastoma tumor suppressor pathway modulates the invasiveness of ErbB2-positive breast cancer. Oncogene 33:3980-91|
|Knudsen, Erik S; Dervishaj, Ornella; Kleer, Celina G et al. (2013) EZH2 and ALDH1 expression in ductal carcinoma in situ: complex association with recurrence and progression to invasive breast cancer. Cell Cycle 12:2042-50|
|Dean, Jeffry L; McClendon, A Kathleen; Knudsen, Erik S (2012) Modification of the DNA damage response by therapeutic CDK4/6 inhibition. J Biol Chem 287:29075-87|
|Witkiewicz, Agnieszka K; Ertel, Adam; McFalls, Jeanne et al. (2012) RB-pathway disruption is associated with improved response to neoadjuvant chemotherapy in breast cancer. Clin Cancer Res 18:5110-22|
|Dean, Jeffry L; McClendon, A Kathleen; Hickey, Theresa E et al. (2012) Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. Cell Cycle 11:2756-61|
|Knudsen, Erik S; Pajak, Thomas F; Qeenan, Maria et al. (2012) Retinoblastoma and phosphate and tensin homolog tumor suppressors: impact on ductal carcinoma in situ progression. J Natl Cancer Inst 104:1825-36|
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