Many chemotherapy drugs act against cancer cells by causing damage to the DNA. Resistance to chemotherapy is a major clinical obstacle in cancer treatment. The mechanisms of chemoresistance in cancer patients are not fully understood, leading to urgent needs for determining factors that control drug response and developing novel therapies to enhance the treatment efficacy. Signaling from transforming growth factor (TGF) ?, a tumor suppressor in normal cells, is hijacked in cancer to promote disease progression. In breast cancer, TGF- ? is linked to poor clinical outcomes and chemoresistance through mechanisms that remain largely unknown. Our previous studies indicate that in breast cancer cells, TGF- ? induces microRNAs (miR-21 and miR-181) that target the DNA damage sensors ATM and MSH2, and may therefore regulate cancer response to genotoxic chemotherapy. The goals of this study are to dissect the molecular mechanism of TGF-2-mediated chemoresistance, and to explore potential therapies to enhance drug efficacy.
In Aim 1, TGF- ? action on cell response to various DNA-damaging treatments and to inhibition of poly(ADP-ribose) polymerase (PARP) will be determined in breast cancer cells with different p53 status using established molecular and cellular biology assays. The role of the TGF- ? -regulated miRNAs and the ATM/MSH2 pathways will be determined using gene knockdown and overexpression strategies.
In Aim 2, the hypothesis that enhanced SMAD2/3 binding to their RNA targets mediates TGF- ? 's functional shift in cancer cells towards inducing miRNA regulation and chemoresistance will be examined. Breast cancer cells expressing various levels of the SMAD2/3 cofactors (i.e., SMAD4, Drosha and p68) will be examined for their dynamic regulation of SMAD2/3 function and TGF-2 effect.
In Aim 3, the effect of TGF- ? on chemotherapy response and the mechanism identified in the first two aims will be evaluated in animal tumor models. Novel strategies to therapeutically suppress this TGF- ? function and enhance the treatment efficacy will be explored. This study will enable better understandings of drug resistance and of TGF- ? signaling as both a marker and a target in cancer treatment. Although the mechanism identified herein may have a general application to understanding cancer and defining treatments, our study has added significance for clinically aggressive, hard-to-treat basal- like (mainly triple-negative) breast cancer that often experience active TGF- ? signaling. This study will provide novel insight into the functional switch of TGF- ? in cancer via SMAD2/3-mediated miRNA processing. Understanding TGF-2-mediated chemoresistance may reveal novel therapeutic targets and strategies that will enhance the chemotherapy efficacy for cancers that lack targets for systemic treatments. Our long-term objectives are to validate this mechanism in primary cancers and establish standard approaches to identify patients suitable for therapies targeting TGF- ? 's drug resistant effect, and to understand the global effect of TGF- ? -mediated miRNA dysregulation in human cancer.
The transforming growth factor (TGF) ? has been associated with poor prognosis and chemoresistance in cancer patients, but the mechanisms remain largely unknown. Recent studies suggest that in breast cancer cells, TGF-? may induce tolerance to the DNA damage caused by chemotherapy drugs through regulating microRNAs (miR-21 and miR-181). In the proposed study, we will carry out in-depth dissection of this mechanism of drug resistance, and will explore novel therapeutic strategies to enhance the efficacy of chemotherapy in breast cancer.
|Yan, Wei; Wu, Xiwei; Zhou, Weiying et al. (2018) Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells. Nat Cell Biol 20:597-609|
|Liu, Liang; Yang, Lin; Yan, Wei et al. (2018) Chemotherapy Induces Breast Cancer Stemness in Association with Dysregulated Monocytosis. Clin Cancer Res 24:2370-2382|
|Chin, Andrew R; Wang, Shizhen Emily (2016) Cancer-derived extracellular vesicles: the 'soil conditioner' in breast cancer metastasis? Cancer Metastasis Rev 35:669-676|
|Chin, Andrew R; Wang, Shizhen Emily (2016) Cancer Tills the Premetastatic Field: Mechanistic Basis and Clinical Implications. Clin Cancer Res 22:3725-33|
|Chin, Andrew R; Fong, Miranda Y; Somlo, George et al. (2016) Cross-kingdom inhibition of breast cancer growth by plant miR159. Cell Res 26:217-28|
|Fong, Miranda Y; Zhou, Weiying; Liu, Liang et al. (2015) Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol 17:183-94|
|Liu, Liang; Zhou, Weiying; Cheng, Chun-Ting et al. (2014) TGF? induces ""BRCAness"" and sensitivity to PARP inhibition in breast cancer by regulating DNA-repair genes. Mol Cancer Res 12:1597-609|
|Zhou, Weiying; Fong, Miranda Y; Min, Yongfen et al. (2014) Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25:501-15|
|Chow, Amy; Zhou, Weiying; Liu, Liang et al. (2014) Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-?B. Sci Rep 4:5750|