Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

Bronsveld, Heleen K; ter Braak, Bas; Karlstad, Øystein; Vestergaard, Peter; Starup-Linde, Jakob; Bazelier, Marloes T; De Bruin, Marie L; de Boer, Anthonius; Siezen, Christine L E; van de Water, Bob; van der Laan, Jan Willem; Schmidt, Marjanka K

doi:10.1186/s13058-015-0611-2

Table 1 Overview of in vitro studies in breast cancer cell lines on the mitogenic potential of insulin analogues

From: Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

Author, year	Cell line	INSR/IGF1R	Method	Starvation	Stimulation time	Refreshment of medium	Type of stimulation medium	Presence phenol red	Analogues tested	Concentrations tested nM	Mitogenic response	Sig.	PI3K pathway*	MAPK pathway*
Milazzo et al., 1997 [26]	MCF7^A	1:4	[3H]Thymidine incorporation	Yes	24 hrs stim 2 hrs measure	Yes	MEM DME/F12 + 0.1 % BSA	Yes	AspB10	10	↑^A,B	Yes
	MCF7^A	1:0.8	DNA measurement	Yes	3−5 days	Yes, every two days	MEM DME/F12 + 0.1 % BSA	Yes	AspB10	0.01−10	↑^A,B	yes
	MCF10^B		Colony forming assay	No	2 weeks	Yes, every two days	MEM DME/F12 + 2 % BSA	Yes	AspB10	100	↑^A -^B	Yes
Staiger et al., 2007 [32]	MCF7^A	-	[3H]Thymidine incorporation	48h^A	20 hrs stim 4 hrs measure	Yes	DME/F12 SFM	No	Glargine	10, 50, 100	↓^A	No
	MCF10^B	-	MTT	24h^B	4 days	Yes, every two days	DME/F12 SFM	No	Glargine	1, 5, 10, 25	↑^A,B	No
	MCF10^B	-	MTT	No	4 days	Yes, every two days	DME/F12 SFM	No	Glargine	1, 5, 10, 25	↑^A,B	No
Liefvendahl et al., 2008 [24]	MCF7 SKBR-3	1:20	[3H]Thymidine incorporation	24 hrs	21 hrs stim 3 hrs measure	No	DMEM SFM	No	Glargine	0.01−100	-
Liefvendahl et al., 2008 [24]	MCF7 SKBR-3	1:1.8	[3H]Thymidine incorporation	24 hrs	21 hrs stim 3 hrs measure	No	DMEM SFM	No	Glargine	0.01−100	-
Mayer et al., 2008 [25]	MCF7^A	1:3	Cristal violet cell staining	No	4 days	No	DMEM + 1 % SD-FBS	No	Aspart	1.5^A,B
	MCF7^A	1:3							Lispro	15^A,B
	MCF10A^B	1:1.2							Glargine	1500^C	↑^A	Yes^A
	MCF10A^B	1:1.2							Glulisine
	T47D^C	1:2							Detemir
Shukla et al., 2009 [31]	MCF7^A	-	Cristal violet cell staining	24 hrs	3 days^A	Yes, every 24 hrs	DMEM + 2 % CDFBS	No	Aspart	1.5, 15, 150,	↑^A	No
					3 days^A		DMEM + 2 % CDFBS		Lispro	1500	-
					2 days^B		MEGM^B		Glargine		↑^A	yes
					2 days^B		MEGM^B		Detemir		↓^A	No
	MCF10A^B	-	WB	24 hrs	10 min	-	DMEM + 2 % CDFBS	No	Aspart				-	-
							DMEM + 2 % CDFBS		Lispro				-	-
							MEGM^B		Glargine			Yes	↑^A,B	↑^A
							MEGM^B		Detemir			Yes	↓^A	-
Shukla et al., 2009 [30]	MCF7^A	-	Cristal violet cell staining	24 hrs	3 days^A	Yes, every 24 hrs	DMEM + 2 % CDFBS	No	Glulisine	1.5, 15, 150, 1500	↓^AB	No
	MCF10A^B	-	Cristal violet cell staining	24 hrs	2 days^B	Yes, every 24 hrs	MEGM	No	Glulisine	1.5, 15, 150, 1500	↓^AB	No
			MMOC/ki67 nuclei count	No	3 days	No	Waymouth medium SFM		Glulisine	750	↓	No
			WB	24 hrs	10 min	-	DMEM + 2 % CDFBS^A	No	Glulisine			Yes	↓^AB	↓^AB
			WB	24 hrs	10 min	-	MEGM^B	No	Glulisine			Yes	↓^AB	↓^AB
Weinstein et al., 2010 [35]	MCF7	-	Cell counting	No	72 hrs	Yes every day	DMEM/SFM		Glargine	100	↑	No
Weinstein et al., 2010 [35]	MCF7	-	Cell counting	No	72 hrs	Yes every day	DMEM/SFM		Detemir	100	↑	No
Oleksiewicz et al., 2011 [27]	MCF7	-	FACS	72 hrs	24−30 hrs	No	DMEM + 0.1 % FCS	No	X10	0.074−2	↑	Yes
Oleksiewicz et al., 2011 [27]	MCF7	-	WB	72 hrs	20−40 min	No	DMEM + 0.1 % FCS	No	X10	0.67, 2		Yes	↑	↑
Teng et al., 2011 [33]	MCF7^A	-	MTT	24 hours	2 days	Yes, every two days	RPMI + 0.5 % CS-FBS	No	Glargine	20−200	↑^A	Yes
			MTT	24 hours	2 days	Yes, every two days	RPMI + 0.5 % CS-FBS	No	Glargine	20−200	↑^A	Yes
			WB	No	0, 30, 60, 120, 240 min	No	RPMI + 0.5 % CS-FBS	No	Glargine	100nM	↑^A
			FACS anti-apoptotic	No	48 hrs	No	RPMI + 0.5 % CS-FBS		Glargine		↑^A anti-Apoptotic response	Yes
Glendorf et al., 2012 [21]	HMEC	1:20	[3H]Thymidine incorporation	No	70 hrs stim 2 hrs measure	No	MEGM	?	B10A,	0.0001−1000	↓
									B10R,		↓
									X10,		↑
									B10Q,		↑
									B10E,		↑
									B10H,		↓
									B10I,		↓
									B10F,		↓
									B10W,		↓
									B10V		↓
Hansen et al., 2012 [22]	HMEC^A	1:21	[3H]Thymidine incorporation	24 hrs	70 hrs stim 2 hrs measure	No	MEGM	No	Detemir	0.001−1000	↓^A	Yes
									Glargine		↑^A	Yes
									X10		↑^A	Yes
Knudsen et al., 2012 [23]	MCF7^A	-	[3H]Thymidine incorporation	2 hrs	24 hrs stim 2 hrs measure	No	DMEM + 0.1 % serum	No	S961	0.0001−100	↑^A
Pierre-Eugene et al., 2012 [28]	MCF7^A	-	BRET-PIP₃	No	45 min	No	DMEM/F12 + 5 % FBS	?	Aspart				-
	MDA-MB-231^B	-							Lispro				-
									Glargine			Yes	↑^A
									M1				↓^A
									M2				↓^A
									Glulisine			Yes	↓^A
									Detemir			Yes	↓^B
			WB	12	5 or 20 min	No	DMEM/F12	?	Glargine				↑^A	↑^A
							SFM		M1				-	-
							SFM		M2				-	-
			[¹⁴C]Thymidine incorporation	4 hrs	19 hrs stim 6 hrs measure	No	DMEM/F12 SFM	?	Glargine	0.01−1000	↑^A
									M1		-
									M2		-
Gallagher et al., 2013 [20]	MET1		WB	1 hr	10 min	No	DMEM + 0.1 % BSA		X10	10	↑	Yes
Gallagher et al., 2013 [20]	MVT1		WB	1 hr	10 min	No	DMEM + 0.1 % BSA		X10	10	↑	Yes
Ter Braak et al., 2014 [34]	MCF7 IGF1R^A	1:25	WB		30 min	No	RPMI + 5 % CDFBS	No	Aspart	10, 33, 100			-	-
	MCF7 INSR^B	1:0.02							Lispro			Yes	↑^A	-
	MCF7 INSR^C	1:0.07							Glargine			↑^A	↑^ABC
									M1				-	-
									M2				-	-
									Glulisine			-	-
									Detemir			Yes	↓^{AB C}	↓^ABC
									X10			Yes	↑^A	↑^ABC
			SRB	24 hrs	4 days	Yes	RPMI + 5 % CDFBS	No	Aspart	0.01−100	-
									Lispro		-
									Glargine		↑	Yes
									M1		-
									M2		-
									Glulisine		-
									Detemir		↓	Yes
									X10		↑	Yes
Sciacca et al., 2014 [29]	MCF7^A	1:6	BRDU incorporation	24 hrs	12 hrs, 6 hrs measure	No	MEM SFM	?	Aspart	5 nM	↓^A –^B,C,D
	MDA-MB-	1:2							Lispro	(only detemir	-^A,C,D ↑^B	Yes^B
	157^B								Glargine	at 19 nM)	-^A,C,D ↑^B	Yes^B
	MDA-MB-468^C	1:0.2							M1		-^A,B,D ↓^C
	T47D^D	1:8							M2		↑^A -^B,D ↓^C
									Glulisine		-^A,C,D ↑^B	Yes^B
									Detemir		-^A,C,D ↑^B	Yes^B
									X10		↑^A,B –^c,D	Yes^B
			Collagen invasion assay (Boyden chamber technique)	No	18 hrs	No	MEM SFM	?	Aspart		-^A,D, ↑^B,C
									Lispro		-^A,D ↑^B,C
									Glargine		↑^A,B,C ↓^D
									M1		↑^A,C –^B,D
									M2		-^A,D ↑^B,C
									Glulisine		↓^A,D ↑^B,C
									Detemir		↑^A,B,C,D
									X10		↑^A,B,C,D

^A/BOften studies used multiple cell lines. ^{A, B, C, D} Specific cell line for cell-line-specific conclusions. *Some studies used a specific experimental setup that allowed discrimination between the involvement of different pathways. For all these studies the p-ERK and p-AKT served as biomarker for activation of mitogen-activated protein kinase (MAPK) or phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), respectively. IGF1R insulin-like growth factor-1 receptor, BRDU 5-Bromo-2’-deoxyuridine, RPMI Roswell Park Memorial Institute medium, MTT Microculture Tetrazolium proliferation Assay, WB Western Blot, BRET-PIP Bioluminescence Resonance Energy Transfer assay in which the phophatidylinositol-3 phosphate (PIP(3)) production was monitored, SRB SulfoRhodamine B proliferation assay, MEGM Mammary Epithelial Cell Growth Medium, MEM Minimum Essential Medium, SFM Serum Free Medium, CDFBS Charcoal-Dextran-Treated Fetal Bovine Serum, Sig Significant.

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