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

Table 2 Overview of in vivo studies in animals on the correlation of insulin analogues and breast cancer

Author, year	Model	Number of animals per treatment group	Tissues analysed	Time points sampling	Analogues tested	Dose tested nM	Method	Proteins analysed	Carcinogenic potential	Sig.	Tumour characteristics
Stammberger et al., 2002 [37] (re-evaluation in 2012) [38]	Sprague–Dawley rats and Wistar rats and NMRI mice	5−30	No further tumour characterisation	Follow up of 2 years	Glargine	2, 5, 12.5 IU/Kg	Spontaneous mammary gland tumour formation upon treatment		-		MG adenoma, fibroadenoma, adenocarcinoma
Gallagher et al., 2012 [36]	Orthotopic mammary tumour weight and hyperinsulinaemic MKR mice	3−4	Mammary gland	0−25 days	AspB10	12.5 IU/kg	Tumour volume measurement		↑	Yes
			Lung metastasis			2x/day	Counting lung metastases		↑	No
							WB receptor activation	p-INSR	↑	Yes
								p-IGF1R
								p-Akt	↑	Yes
								p-Erk	-
Tennagels et al., 2013 [39]	Female Sprague–Dawley rats	3−4	Mammary gland	60 min	Glargine	12.5, U/kg	WB kinase activation	p-INSR	-
Tennagels et al., 2013 [39]	Female Sprague–Dawley rats	3−4	Mammary gland	60 min	AspB10			p-IGF1R	↑	Yes
Ter Braak et al., 2015 [40]	p53^R270H/+WAPCre FVB mice	40	Mammary gland tumors	Chronic exposure till MG tumor development	Glargine	12.5-15 IU/kg	Tumour latency time		↑	No	Majority aggressive EMT no correlation pathology and treatment
					AspB10	150-200 IU/kg			↑	Yes
							WB protein expression profiling	INSR
								IGF1R,
								Erk,
								p-Erk,	↑	Yes
								Akt,
								p-Akt,	↑	Yes
								EGFR,
								ER,
								E-cad,
								N-cad, Her2

IGF1R insulin-like growth factor-1 receptor, EGFR epidermal growth factor receptor, ERK extracellular signal-related kinase, ER oestrogen receptor, E-cad E-cadherin, N-cad N-cadherin, Her2 human epithermal growth factor receptor 2

ISSN: 1465-542X