Multidrug-resistant breast cancer: current perspectives

Figures & data

Figure 1 Estrogen, HER2 signalling, and the PI3K/Akt pathway in drug-resistant breast cancer.

Notes: ER can activate gene transcription by nuclear translocatin following ligand binding (1) or as a result of receptor phosphorylation in the absence of ligand (2). ERs may also be found associated with the plasma membrane in the presence of SRC and other adaptor proteins. Here, ligand binding triggers nongenomic effects via activation of signaling pathways, including the PI3K/Akt and the Ras/MAPK pathways (not shown) (3). These pathways are also activated by ligand binding to the GPR30 (4) and by growth factor binding to receptor tyrosine kinases, including HER2, inducing autophosphorylation and downstream signalling (5). The PI3K/Akt pathway (6) as indicated is a covergence point in the mechanisms implicated in drug resistance in the three types of breast cancer discussed here, as pathway hyperactivity frequently occurs with multiple downstream effects (7). Data from^{9–11,25,26,30,35,36,42,57,60}
Abbreviations: BAD, Bcl-2-associated death promoter; DMNTs, DNA methyltransfereases; E₂, estrogen; ER, estrogen receptor; GF, growth factor; GPR30, G-protein coupled receptor 30; GSK3B, glycogen synthase kinase 3 beta; HER2, human epidermal growth factor receptor 2; IGF-1R, insulin-like growth factor receptor 1; MAPK, mitogen-activated protein kinase; mTORC1, mammalian target of rapamycin complex 1; P-gp, P-glycoprotein; PI3K, phosphatidylinositide 3-kinase; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase; SRC, steroid receptor coactivator.

Table 1 miRNA associated with drug resistance in breast cancer

miRNA	Expression change associated with resistance	Target genes	References
Lin 28	Upregulated	CDKN1A (p21), RB1, Let-7	^Citation91
miR-10a	Upregulated	Not stated	^Citation92
miR-21	Upregulated	PTEN, PDCD4	^Citation92,Citation93
miR-22	Upregulated	Not stated	^Citation92
miR-29a	Upregulated	PTEN	^Citation92,Citation94
miR-30c	Downregulated	TWF1 (Twinflin 1)	^Citation95
miR-31	Downregulated	PKC epsilon (PRKCE)	^Citation96
miR-34a	Downregulated	NOTCH1	^Citation97
miR-93	Downregulated	Not stated	^Citation92
miR-125b	Upregulated	E2F3	^Citation92,Citation98
miR-128	Downregulated	BMI1, ABCC5	^Citation99
miR-137	Downregulated	YB-1 (P-gp indirectly)	^Citation100
miR-181	Upregulated	Not stated	^Citation92
miR-181a	Downregulated	ABCG2 (BCRP)	^Citation101
miR-200a and miR-200b	Downregulated	ZEB1/2	^Citation92,Citation102
miR-200c	Downregulated	ZEB1, CDH1 (E-cadherin), PTEN, NTRK2 (TrkB), BMI1	^Citation62,Citation63,Citation92, ^Citation102,Citation103
miR-203	Upregulated	SOC3	^Citation104
miR-205	Downregulated	Not stated	^Citation92
miR-210	Upregulated	Not stated	^Citation105
miR-222	Upregulated	PTEN	^Citation92,Citation94
miR-298	Downregulated	MDR1 (P-gp)	^Citation106
miR-375	Downregulated	MTDH (metadherin)	^Citation107
miR-487a	Downregulated	ABCG2 (BCRP)	^Citation108
miR-505	Downregulated	AKT3	^Citation109
miR-633	Upregulated (hypomethylated)	HSPG2	^Citation110

Notes: A number of miRNAs have shown altered expression levels in drug-resistant forms of breast cancer in both cells and patients. The table contains those reported since 2011 (for prior studies we refer the reader to Kutanzi et al⁵⁶) together with their delineated target genes.

Abbreviations: BCRP, breast cancer resistance protein; miRNA, micro-RNAs; PDCD4, programmed cell death 4; P-gp, P-glycoprotein; PTEN, phosphatase and tensin homolog.

Table 2 Genes with altered methylation status in drug-resistant breast cancer

Gene	Protein	Hypermethylated/hypomethylated	References
ABCB1 (MDR1) Upstream promoter	P-glycoprotein	Hypomethylated	^Citation57,Citation58,Citation111^–^Citation114
ABCB1 (MDR1) Alternative Downstream promoter	P-glycoprotein	Hypermethylated	^Citation111
ACVR1	Activin A receptor	Hypomethylated	^Citation115
APC	Adenomatous polyposis coli	Hypomethylated	^Citation113
TUBA1A	α-Tubulin	Hypermethylated	^Citation115
AVEN	Cell death regulator Aven (PDCD12)	Hypermethylated	^Citation115
BAD	BCL2-associated agonist of cell death	Hypermethylated	^Citation115
BRCA1	BRAC1	Hypermethylated	^Citation113
CDH1	E-cadherin	Hypermethylated	^Citation113
CDK10	Cyclin-dependent kinase 10	Hypermethylated	^Citation116
CXCR4	Stromal cell-derived factor 1 receptor	Hypomethylated	^Citation115
ESR1	ERα	Hypermethylated	^Citation113,Citation115
ESR2	ERβ	Hypermethylated	^Citation117,Citation118
FTH1	Ferritin heavy chain	Hypomethylated	^Citation115
FOXK1	Forkhead box protein k1	Hypomethylated	^Citation115
GSTP1	Glutathione S-transferase pi 1	Hypomethylated	^Citation57,Citation113
HIC1	Hypermethylated in cancer 1	Hypomethylated	^Citation113
IL2	Interleukin 2	Hypermethylated	^Citation115
LEP	Leptin	Hypomethylated	^Citation115
MGMT	6-O-methylguanine-DNA methyltransferase	Hypomethylated	^Citation57,Citation119
NAT1	N-acetyltransferase 1	Hypermethylated	^Citation120
CDKN1A	p21	Hypermethylated	^Citation121
TP73	p73	Hypermethylated	^Citation115
PLAU	Plasminogen activator urokinase	Hypomethylated	^Citation57,Citation113
PGR	Progesterone receptor	Hypermethylated	^Citation122
TFF1	pS2 (trefoil factor 1)	Hypermethylated	^Citation123
ATP2B4	Sarcolemmal calcium pump	Hypermethylated	^Citation123
DUSP7	Dual-specific phosphatase 7	Hypermethylated	^Citation123
GDF15	Growth differentiation factor 15	Hypermethylated	^Citation123
PSAT1	Phosphoserine aminotransferase 1	Hypomethylated	^Citation124
PTEN	PTEN	Hypermethylated	^Citation78
RAB6C	WTH3	Hypermethylated	^Citation113,Citation125,Citation126
RASAL1	Ras protein activator-like 2 (GAP1)	Hypermethylated	^Citation113
ARHGEF2	Rho/rac GEF2	Hypermethylated	^Citation115
RASSF1	Ras association domain containing protein 1	Hypomethylated	^Citation113
RFC1	Replication factor C1	Hypermethylated	^Citation127
SDK2	Sidekick 2	Hypomethylated	^Citation115
SULF2	Sulfatase 2	Hypermethylated	^Citation113
TGM2	Tissue transglutaminase	Hypomethylated	^Citation113,Citation115
UTRN	Utrophin	Hypomethylated	^Citation115

Note: Hypomethylation results in gene overexpression as DNA methylation reduces gene transcription; consequently, hypermethylation effectively leads to gene silencing.

Abbreviations: ER, estrogen receptor; PTEN, phosphatase and tensin homolog.

Table 3 Inhibitors of the PI3K/Akt pathway currently undergoing clinical trials

Drug	Target	Breast cancer selection criteria	Combination therapies	Phase	Trial identifiers
AZD5363	Akt	ER+	Paclitaxel/none	I	NCT01625286, NCT01226316
GSK2110183	Akt	Drug resistant	None	I	NCT01476137
GSK2141795	Akt	Not stated	None	I	NCT00920257
MK2206	Akt	ER+	Lapatnib ditosylate/paclitaxel/anastrozole/letrozole/exemestane/fulvestrant/none	II	NCT01245205, NCT01277757, NCT01776008, NCT01344031
		HER2+	Lapatnib ditosylate/trastuzumab	I	NCT01705340, NCT01281163
		Not stated	Paclitaxel	Ib	NCT01263145
Triciribine Phosphate Monohydrate	Akt	Not stated	Paclitaxel/doxorubicin/cyclophosphamide	I/II	NCT01697293
BAY 80-6946	PI3K	Not stated	Paclitaxel	I	NCT01411410
BKM120	PI3K	ER+	Fulvestrant/letrozole	I, III	NCT01339442, NCT01248494, NCT01633060, NCT01610284
		HER2	Lapatnib/trastuzumab/capecitabine	I/II	NCT01589861, NCT01132664
		Trastuzumab-resistant HER2+	Trastuzumab + paclitaxel	I, II	NCT01285466, NCT01816594
		HER2−	Paclitaxel	II	NCT01572727
		Triple-negative	Postchemotherapeutics	I, II	NCT01629615
BYL719	PI3K	ER+/HER2−	Letrozole/fulvestrant	I	NCT01791478, NCT01219699
GDC-0941	PI3K	Not stated	Trastuzumab, paclitaxel, bevacizumab	I	NCT00960960
		ER+	Fulvestrant	II	NCT01437566
XL147	PI3K	ER+ HER2+	Letrozole	I	NCT01082068
CC-223	mTOR	ER+	Unresponsive tumors	I/II	NCT01177397
Everolimus	mTOR	ER+/HER2+/−	Endocrine therapies (tamoxifen)/bevacizumab, lapatnib	II, III	NCT01298713, NCT01805271
		ER+, AI–resistant	Fulvestrant/chemotherapeutics/exemestane	II, III	NCT01797120, NCT01088893, NCT00863655 and NCT01626222
		HER2+	Paclitaxel, trastuzumab	III	NCT00876395
		HER2−	Vinorebine	II	NCT01520103
		Triple-negative	Gemcitabine, cisplatin	I	NCT01939418
Rapamycin	mTOR	HER2+	Trastuzumab	II	NCT00411788
Temsirolimus	mTOR	ER+	Letrozole	II	NCT00062751
		HER2+/triple negative	Neratinib	I/II	NCT01111825
Ridaforolimus	mTOR	ER+	Dalotuzumab, exemestane	II	NCT01234857
BEZ235	PI3K/mTOR dual inhibitor	ER	Letrozole/everolimus	I	NCT01248494, NCT01482156
		HER2+	Paclitaxel, trastuzumab	I	NCT01285466
		HER2−	Paclitaxel	I/II	NCT01495247
GDC-0980	PI3K/mTOR dual inhibitor	ER+	Fulvestrant	II	NCT01437566
XL765	PI3K/mTOR dual inhibitor	ER+ HER2−	Letrozole	II	NCT01082068

Notes: The alterations to the PI3K/Akt pathway are common factors in the different subtypes of breast cancer and also have important roles in mediating drug resistance (see text for details). Subsequently, this pathway is a promising therapeutic target to overcome drug resistance with a variety of compounds in clinical trials. Data obtained from the ClinalTrials.gov database.

Abbreviations: AI, aromatase inhibitor; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; mTOR, mammalian target of rapamycin complex 1.

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