Project 2: p63/p73 Signaling Axis as a Target for Treatment of Triple-Negative Breast Cancer
A.1 Human health challenge. Triple-negative breast cancers—that is, tumors that are negative for estrogen and progesterone receptor expression and HER2 gene amplification—have a distinct gene expression profile, exhibit a poor prognosis, and do not respond to commonly used chemotherapeutic agents. The percentage of triple negative breast cancers varies by race and is 25% in African Americans, 17% in Hispanics, 12% in Asian/Pacific Islanders, and 11% in Caucasians1. There is a major need to better understand the molecular basis of this type of breast cancer as well as develop new therapeutic strategies against it.
The p53 family of transcription factors, p53, p63, and p73, are key regulators of tumor suppressor signaling pathways in breast cancer2. The p53 tumor suppressor is mutated in ~30% of breast cancers3, but incidence of p53 mutation is higher in aggressive (ER)-negative breast cancers4 and is strongly associated with the 'basal-like' group4,5. Triple negative tumors will have differential gene expression patterns depending on p53 mutational status and expression of the two other p53 family members, p63 and p73. The p63 protein is an essential regulator of mammary gland development, and recent evidence from our laboratory and others supports a role for p63 in epithelial cell survival. p63 is not detectable in the majority of invasive breast carcinomas; however, p63 is expressed in ~25%-30% of triple negative, basal-like tumors6-14. Our laboratory and others have shown that the p63 isoform expressed in breast tumors (ΔNp63α) has potent transcriptional repression activity15-18. Further, in a fraction of basal-like tumors, p63 is coordinately expressed with p73 and may antagonize p73-mediated apoptosis19. In this application, we propose that the p63/p73 signaling axis is a robust molecular target for the treatment of triple negative tumors. We will determine if modulation of this axis plays a critical role in drug-induced breast tumor cell apoptosis.
We have developed p63 and p73 gene expression signatures and our preliminary data suggest that these signatures may segregate triple negative tumors into additional subtypes that could aid therapeutic decision-making. Further, using a gene expression–based chemical genomics approach, we have identified a class of drugs (insulin sensitizers, mTOR inhibitors) that modulates p73 activity. We have also identified drugs that can elevate p73 and decrease p63, which is of relevance given that these agents may ‘tip’ the p63/p73 signaling axis towards pro-apoptotic signaling in triple negative breast cancer cells. Based on the recent findings from our laboratory and others we propose the following interrelated hypotheses:
In triple negative, basal-like tumors that express both p63 and p73, p63 promotes tumor cell survival through repression of p73. Further, the combined use of drugs that can target the p63/p73 signaling axis at multiple points will have synergistic activity. In the remaining fraction of triple negative tumors that lack p63 expression, but express p73, other pathways are selected that modulate p73 apoptotic activity and promote tumor cell survival.
Specific Aim 1: To determine the degree of tumor response to neoadjuvant cisplatin, paclitaxel, and the TOR inhibitor everolimus (RAD001) versus cisplatin and paclitaxel therapy in patients with triple negative breast tumors.
Specific Aim 2: To determine if gene expression profiling can sub-classify triple negative, basal-like cancers and identify gene expression signatures, such as those of p63 and p73, that will predict sensitivity and response to neoadjuvant, preoperative therapy in triple negative breast cancers.
Specific Aim 3: To analyze a panel of insulin sensitizers for their ability to activate p73 and induce apoptosis alone or in combination with known chemotherapeutic agents in triple negative breast cancer cells. In parallel, we will determine the mechanism by which p73 levels and activity are increased by these drugs.
A.2 Translational Goal and Clinical Impact. The main goal of this project is the identification of effective therapeutic approaches for patients with triple negative breast cancer. Based on our linkage of p73 to the mTOR signaling pathway, we have the potential to uncover a novel combinatorial therapy for this type of breast cancer. Moreover, p63 and p73 gene signatures may assist in identification of patient candidates for this combination as well as guide the future selection of active drugs against triple negative breast cancers.