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Cell & Cellular Life Sciences Journal Research Article 4 min read

Breast Cancer, Chemotherapy and Treatments

Li-Pin Kao*
* Corresponding author
ISSN: 2578-4811  10.23880/cclsj-16000118  Received: February 07, 2018  Published: February 21, 2018
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 13 references
 2 tables
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Keywords
&lt p&gt Breast Cancer Autophagy Autophagy-Related Inhibitors Chemotherapy&lt /p&gt
Abstract

<p>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.</p>

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 the best approach is. 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, 6, 7]. Moreover, Tamoxifen and Faslodex (ICI) both induce autophagy in ER+ breast cancer cells without [3, 5, 8, 9, 10, 11]. There are small molecules which has been in FDA- approval drug lists and applied in clinical trial in different diseases Tables 1 & 2. 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].

Cell & Cellular Life Sciences Journal

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, suggesting a role for autophagy in breast cancer reoccurrence [12]. 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.

NameMechanism
3-Methyladeninephosphoinositide3-kinase (PI3) inhibitorAutophagosome formation
WortmanninPI3-kinase inhibitorAutophagosome formation
LY294002PI3-kinase inhibitorAutophagosome formation
SBI-0206965Unc-51-like kinase 1 (ULK1) InhibitorAutophagosome formation
Spautin-1ubiquitin-specific peptidases (USP10) and
(USP13) inhibitor		Autophagosome formation
SAR405Vacuolar Protein Sorting Protein 18 and 34
(Vps18 and Vps34) inhibitor		Autophagosome formation
NSC185058autophagy-related gene 4 (ATG4) inhibitorAutophagosome formation
VerteporfinUnknownAutophagosome formation and
accumulation
ROC325UnknownLysosome
Lys05UnknownLysosome
ChloroquineUnknownLysosome
HydroxychloroquineUnknownLysosome

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

Reference # at
TreatmentConditionPhase Trial
ClinicalTrials.gov
HCQ + sunitinib malateAdult solid neoplasmINCT00813423
HCQ + vorinostatMalignant solid tumorINCT01023737
HCQ + sirolimus or vorinostatAdvanced cancersINCT01266057
HCQ + Protein kinase B (Akt)
inhibitor		Advanced cancersINCT01480154
MK-2206 dihydrochloride (MK2206)
HCQ as a single agentEstrogen receptor positive breast
cancer		INCT02414776
HCQ + gemcitabineAdvanced adenocarcinomaI/IINCT01506973
HCQ + Interleukin 2(IL-2)Renal cell carcinomaI/IINCT01550367
HCQ + vorinostatColorectal cancerI/IINCT02316340
HCQ + gemcitabine/carboplatinSmall cell lung cancerI/IINCT02722369
HCQ + capecitabinePancreatic carcinomaIINCT01494155
HCQ as a single agentProstate cancerIINCT00726596
HCQ + Abraxane and gemcitabinePancreatic carcinomaIINCT01978184

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

It is very little is known how the manipulation of a biological process toward to potential cancer therapy. As

Cell & Cellular Life Sciences Journal

autophagy activities in different cancer treatment in basic biomedical research and different clinical trials. Given the rapid progress in understanding autophagy in cancer- related researches and what it does, manipulation of autophagy activities in cancer-related research has ready to take off.

Conflicts of Interest

The author indicates no potential conflict of interest

Acknowledgement

The author would like to acknowledge the financial support of the Purdue University for provided support in the form of salaries of KLP listed but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

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  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 Clin 3: 257-275.
  3. Cook KL, Shajahan AN, Warri 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(13): 3337-3349.
  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(1): 3158.
  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(6): 1321-1331.
  6. Thomas S, Thurn KT, Biçaku E, Marchion DC, Munster 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(2): 437-447.
  7. Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA (2009) Autophagy facilitates the development of breast cancer resistance to the anti-HER2 monoclonal antibody trastuzumab. PLoS One 4(7): e6251.
  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(1): 16.
  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(1- 2): 8-20.
  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(3): 400- 403.
  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(9): 2977-2987.
  12. Cook KL, Warri 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): 3222-3232.
  13. Chude CI, Amaravadi RK (2017) Targeting Autophagy in Cancer: Update on Clinical Trials and Novel Inhibitors. Int J Mol Sci 18(6).
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@article{lipin2018,
  title   = {Breast Cancer, Chemotherapy and Treatments},
  author  = {Li-Pin Kao},
  journal = {Cell & Cellular Life Sciences Journal},
  year    = {2018},
  volume  = {3},
  number  = {1},
  doi     = {10.23880/cclsj-16000118}
}
Li-Pin Kao (2018). Breast Cancer, Chemotherapy and Treatments. Cell & Cellular Life Sciences Journal, 3(1). https://doi.org/10.23880/cclsj-16000118
TY  - JOUR
TI  - Breast Cancer, Chemotherapy and Treatments
AU  - Li-Pin Kao
JO  - Cell & Cellular Life Sciences Journal
PY  - 2018
VL  - 3
IS  - 1
DO  - 10.23880/cclsj-16000118
ER  -