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Breast cancer, chemotherapy and treatments

Li-Pin Kao

Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA

Centre for Cancer Research, Purdue University, West Lafayette, Indiana, USA

E-mail : aa

DOI:10.15761/IMM.1000320

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Abstract

Breast cancer, the first most common malignant tumor in women worldwide. Many etiological factors such as a wide spectrum of clinical manifestations caused by family clustering, hormonal factors, physiology changed, environmental inducers, and life styles. Although there are many FDA-approval drugs for breast cancers. Tumors are heterogenous and individual has inherited different genetic background. Thus, it is hard to find an effective treatment and it may recurrent after recovery from first treatment.

Key words

breast cancer, autophagy, autophagy-related inhibitors, chemotherapy

Introduction

The mortality rate exceeds 144,000 cases and most of the breast cancer (BC) cases are resistant to traditional chemotherapy and radiotherapy. A wide variety of chemotherapeutic agents have been tried and are in use, including tamoxifen, docetaxel, anthracyclines (i.e. doxorubicin, and epirubicin), taxanes (i.e. paclitaxel, and docetaxel), 5-fluorouracil, cyclophosphamide, and carboplatin. No regimen has been proved to be curative. Often, the response rate and prolongation of survival are minimal (a few months or less), and there is a significant morbidity associated with poor treatment effects. Surgical resection is considered the first-line options for early tumors, although there is no agreement on which is the best approach. Interestingly, triple negative has been reported has higher chemo-resistance than other type of breast cancers with low autophagy activity [1,2]. Antiestrogen resistant cell lines exhibit increased basal autophagy when compared with their antiestrogen sensitive parental cells [3]. Study has shown to manipulate transient receptor potential channel 5 (TRPC5), a Ca2+ permeable cation channel, which helps in promotes autophagic activity [4]. Studies also demonstrate the breast cancer usually prosurvival after autophagy activity increase by various therapeutics [5-7]. Moreover, Tamoxifen and Faslodex (ICI) both induce autophagy in ER+ breast cancer cells without [3,5,8-11]. There are small molecules which has been in FDA-approval drug lists and applied in clinical trial in different diseases (Table 1 and 2).

Table 1. Autophagy inhibitors during autophagy pathway. Modified from [13].

Name

Mechanism

3-Methyladenine

phosphoinositide3-kinase (PI3) inhibitor

Autophagosome formation

Wortmannin

PI3-kinase inhibitor

Autophagosome formation

LY294002

PI3-kinase inhibitor

Autophagosome formation

SBI-0206965

Unc-51-like kinase 1 (ULK1) Inhibitor

Autophagosome formation

Spautin-1

ubiquitin-specific peptidases (USP10) and (USP13) inhibitor

Autophagosome formation

SAR405

Vacuolar Protein Sorting Protein 18 and 34 (Vps18 and Vps34) inhibitor

Autophagosome formation

NSC185058

autophagy-related gene 4 (ATG4) inhibitor

Autophagosome formation

Verteporfin

Unknown

Autophagosome formation and accumulation

ROC325

Unknown

Lysosome

Lys05

Unknown

Lysosome

Chloroquine

Unknown

Lysosome

Hydroxychloroquine

Unknown

Lysosome

Table 2. Current Hydroxychloroquine (HCQ) clinical trials. Modified from [13]. 

Treatment

Condition

Phase Trial

Reference # at ClinicalTrials.gov

HCQ + sunitinib malate

Adult solid neoplasm

I

NCT00813423

HCQ + vorinostat

Malignant solid tumor

I

NCT01023737

HCQ + sirolimus or vorinostat

Advanced cancers

I

NCT01266057

HCQ + Protein kinase B (Akt) inhibitor

MK-2206 dihydrochloride (MK2206)

Advanced cancers

I

NCT01480154

HCQ as a single agent

Estrogen receptor positive breast cancer

I

NCT02414776

HCQ + gemcitabine

Advanced adenocarcinoma

I/II

NCT01506973

HCQ + Interleukin 2(IL-2)

Renal cell carcinoma

I/II

NCT01550367

HCQ + vorinostat

Colorectal cancer

I/II

NCT02316340

HCQ + gemcitabine/carboplatin

Small cell lung cancer

I/II

NCT02722369

HCQ + capecitabine

Pancreatic carcinoma

II

NCT01494155

HCQ as a single agent

Prostate cancer

II

NCT00726596

HCQ + Abraxane and gemcitabine

Pancreatic carcinoma

II

NCT01978184

Antiestrogen resistant cell lines exhibit increased basal autophagy. Study had demonstrated combination of Tamoxifen or Faslodex (ICI) with hydroxychloroquine (HCQ) had different anti-estrogen responsiveness in vitro or in vivo which may affect by tumor microenvironment (i.e. chemokines, macrophage development/activity [12]. Inhibiting autophagy via autophagy-related genes (i.e. autophagy-related gene (Atg) 5, Atg7, and p62/SQSTM1) silencing potentiated antiestrogen-mediated cell death, indicating that antiestrogen stimulated autophagy is prosurvival and a critical mechanism of therapy resistance [3]. Overall, it indicated that increased in autophagy activity in early recurring breast cancer when compared with breast cancer that never recurs. Moreover, elevated p62 is significantly correlated with poor survival in breast cancer patients [12], suggesting a role for autophagy in breast cancer reoccurrence. Manipulation of autophagy activity can be a potential therapy for chemotherapy in vitro or in vivo. Therefore, diagnosis or detection at an early stage is crucial to allow the application of treatments for increasing the life expectancy of the patient.

Reference

  1. Garbar C (2017) Chemotherapy treatment induces an increase of autophagy in the luminal breast cancer cell MCF7, but not in the triple-negative MDA-MB231. Sci Rep 7: 7201.
  2. O'Reilly EA, Gubbins L, Sharma S, Tully R, Guang MH, et al. (2015) The fate of chemoresistance in triple negative breast cancer (TNBC).BBA Clin3: 257-275. [Crossref]
  3. Cook KL, Shajahan AN, Wärri A, Jin L, Hilakivi-Clarke LA, et al. (2012) Glucose-regulated protein 78 controls cross-talk between apoptosis and autophagy to determine antiestrogen responsiveness. Cancer Res 72: 3337-49. [Crossref]
  4. Zhang P, Liu X, Li H, Chen Z, Yao X, et al. (2017) TRPC5-induced autophagy promotes drug resistance in breast carcinoma via CaMKKbeta/AMPKalpha/mTOR pathway. Sci Rep 7: 3158. [Crossref]
  5. Clarke R, Cook KL, Hu R, Facey CO, Tavassoly I, et al. (2012) Endoplasmic reticulum stress, the unfolded protein response, autophagy, and the integrated regulation of breast cancer cell fate. Cancer Res 72: 1321-31. [Crossref]
  6. Thomas S, Thurn KT, Biçaku E, Marchion DC, Münster PN (2011) Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy. Breast Cancer Res Treat 130: 437-47. [Crossref]
  7. Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA (2009) Menendez, Autophagy facilitates the development of breast cancer resistance to the anti-HER2 monoclonal antibody trastuzumab. PLoS One 4: e6251. [Crossref]
  8. Cook KL, Soto-Pantoja DR, Abu-Asab M, Clarke PA, Roberts DD, et al. (2014) Mitochondria directly donate their membrane to form autophagosomes during a novel mechanism of parkin-associated mitophagy. Cell Biosci 4: 16. [Crossref]
  9. Clarke R, Shajahan AN, Riggins RB, Cho Y, Crawford A, et al. (2009) Gene network signaling in hormone responsiveness modifies apoptosis and autophagy in breast cancer cells. J Steroid Biochem Mol Biol 114: 8-20. [Crossref]
  10. Schoenlein PV, Periyasamy-Thandavan S, Samaddar JS, Jackson WH, Barrett JT (2009) Autophagy facilitates the progression of ERalpha-positive breast cancer cells to antiestrogen resistance. Autophagy 5: 400-3. [Crossref]
  11. Samaddar JS, Gaddy VT, Duplantier J, Thandavan SP, Shah M, et al. (2008) A role for macroautophagy in protection against 4-hydroxytamoxifen-induced cell death and the development of antiestrogen resistance. Mol Cancer Ther 7: 2977-87. [Crossref]
  12. Cook KL, Wärri A, Soto-Pantoja DR, Clarke PA, Cruz MI, et al. (2014) Hydroxychloroquine inhibits autophagy to potentiate antiestrogen responsiveness in ER+ breast cancer. Clin Cancer Res 20(12): 3222-32. [Crossref]
  13. Chude CI, RK (2017) Amaravadi, Targeting Autophagy in Cancer: Update on Clinical Trials and Novel Inhibitors. Int J Mol Sci. [Crossref]

Editorial Information

Editor-in-Chief

Ivan Gout

Article Type

Mini Review

Publication history

Received date: February 03, 2018
Accepted date: February 20, 2018
Published date: February 23, 2018

Copyright

©2018 Li-Pin Kao. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Li-Pin Kao (2018) Breast cancer, chemotherapy and treatments. Integr Mol Med 5: DOI: 10.15761/IMM.1000320

Corresponding author

Li-Pin Kao

Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA

Table 1. Autophagy inhibitors during autophagy pathway. Modified from [13].

Name

Mechanism

3-Methyladenine

phosphoinositide3-kinase (PI3) inhibitor

Autophagosome formation

Wortmannin

PI3-kinase inhibitor

Autophagosome formation

LY294002

PI3-kinase inhibitor

Autophagosome formation

SBI-0206965

Unc-51-like kinase 1 (ULK1) Inhibitor

Autophagosome formation

Spautin-1

ubiquitin-specific peptidases (USP10) and (USP13) inhibitor

Autophagosome formation

SAR405

Vacuolar Protein Sorting Protein 18 and 34 (Vps18 and Vps34) inhibitor

Autophagosome formation

NSC185058

autophagy-related gene 4 (ATG4) inhibitor

Autophagosome formation

Verteporfin

Unknown

Autophagosome formation and accumulation

ROC325

Unknown

Lysosome

Lys05

Unknown

Lysosome

Chloroquine

Unknown

Lysosome

Hydroxychloroquine

Unknown

Lysosome

Table 2. Current Hydroxychloroquine (HCQ) clinical trials. Modified from [13]. 

Treatment

Condition

Phase Trial

Reference # at ClinicalTrials.gov

HCQ + sunitinib malate

Adult solid neoplasm

I

NCT00813423

HCQ + vorinostat

Malignant solid tumor

I

NCT01023737

HCQ + sirolimus or vorinostat

Advanced cancers

I

NCT01266057

HCQ + Protein kinase B (Akt) inhibitor

MK-2206 dihydrochloride (MK2206)

Advanced cancers

I

NCT01480154

HCQ as a single agent

Estrogen receptor positive breast cancer

I

NCT02414776

HCQ + gemcitabine

Advanced adenocarcinoma

I/II

NCT01506973

HCQ + Interleukin 2(IL-2)

Renal cell carcinoma

I/II

NCT01550367

HCQ + vorinostat

Colorectal cancer

I/II

NCT02316340

HCQ + gemcitabine/carboplatin

Small cell lung cancer

I/II

NCT02722369

HCQ + capecitabine

Pancreatic carcinoma

II

NCT01494155

HCQ as a single agent

Prostate cancer

II

NCT00726596

HCQ + Abraxane and gemcitabine

Pancreatic carcinoma

II

NCT01978184