Hereditary breast cancers stem from inherited mutations in susceptibility genes such as BRCA1, BRCA2 and PALB2, which encode large tumor suppressor proteins that play essential roles in homologous recombination (HR)-mediated DNA double strand break repair and cell cycle checkpoint response. Moreover, these proteins also function in oxidative stress response. As a result of seminal discoveries of the role of the BRCA/PALB2 proteins in DNA repair, the repair defect of the deficient tumor cells is now being targeted using platinum drugs and PARP inhibitors. However, the mutant cells tend to develop resistance to both types of drugs. Thus, for both prevention and better treatment of the cancers, it is imperative to find new avenues to selectively kill the mutant cells, preferably ones that taret different pathways. Using our Palb2 conditional knockout mouse model, we have identified autophagy as a protective mechanism for Palb2-deficient cells during breast cancer development. Our results suggest that, in the face of DNA damage and oxidative stress elicited by PALB2 loss, autophagy opposes a p53-mediated barrier to facilitate tumorigenesis. Based on the similarities between the molecular functions and clinical phenotypes of BRCA1/2 and PALB2, we hypothesize that autophagy inhibition may prevent the development and impede the progression of both PALB2- and BRCA-associated hereditary breast cancers. In this proposal, we will use conditional knockout and inducible knockdown mouse models to test the hypothesis, and deploy a combination of in vivo, ex vivo and in vitro analyses and metabolomics to identify the molecular mechanisms by which autophagy promotes the development of cancers associated with HR deficiency and oxidative stress.
In Aim 1, we will define the role of autophagy in mammary epithelial cell fate following PALB2 and BRCA1/2 loss.
In Aim 2, we will define the role of autophagy in Palb2- and Brca1/2- associated mammary tumor development and explore the potential of autophagy inhibition for prevention and treatment.
In Aim3, we will investigate the mechanisms of autophagy-mediated promotion of Palb2- and Brca1/2-associated mammary tumorigenesis.
Inherited mutations in BRCA1, BRCA2 and PALB2 account for up to 5% of all breast cancer, and epigenetic silencing of BRCA1 or PALB2 occur in another 20-30% of the disease. Additionally, mutations in these genes also increase the risk of ovarian, pancreatic, prostate and other cancers. Results from this study may provide a scientific basis and preclinical reference for the rational design of novel, autophagy-targeting approaches for the prevention and better treatment of the cancers. Insights from this study may also apply to other, hereditary or sporadic cancers associated with DNA damage and oxidative stress, and therefore have broader implications.
|Anantha, Rachel W; Simhadri, Srilatha; Foo, Tzeh Keong et al. (2017) Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance. Elife 6:|
|Foo, T K; Tischkowitz, M; Simhadri, S et al. (2017) Compromised BRCA1-PALB2 interaction is associated with breast cancer risk. Oncogene 36:4161-4170|
|Lu, Kevin; Alcivar, Allen L; Ma, Jianglin et al. (2017) NRF2 Induction Supporting Breast Cancer Cell Survival Is Enabled by Oxidative Stress-Induced DPP3-KEAP1 Interaction. Cancer Res 77:2881-2892|
|Buisson, Rémi; Niraj, Joshi; Rodrigue, Amélie et al. (2017) Coupling of Homologous Recombination and the Checkpoint by ATR. Mol Cell 65:336-346|
|Kimmelman, Alec C; White, Eileen (2017) Autophagy and Tumor Metabolism. Cell Metab 25:1037-1043|
|Lashinger, Laura M; O'Flanagan, Ciara H; Dunlap, Sarah M et al. (2016) Starving cancer from the outside and inside: separate and combined effects of calorie restriction and autophagy inhibition on Ras-driven tumors. Cancer Metab 4:18|
|Amaravadi, Ravi; Kimmelman, Alec C; White, Eileen (2016) Recent insights into the function of autophagy in cancer. Genes Dev 30:1913-30|
|Kumar, Namit; Srivillibhuthur, Manasa; Joshi, Shilpy et al. (2016) A YY1-dependent increase in aerobic metabolism is indispensable for intestinal organogenesis. Development 143:3711-3722|
|White, Eileen (2016) Autophagy and p53. Cold Spring Harb Perspect Med 6:a026120|
|Mehnert, Janice M; Panda, Anshuman; Zhong, Hua et al. (2016) Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer. J Clin Invest 126:2334-40|
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