Role of sex steroid receptors in pathobiology of hepatocellular carcinoma

Table 1 Estrogen receptor expression in liver tissue samples from HCC patients

Subcellular localization	Method	ER subtype/Antibody source	n	Subjects	Positive cases	Country and area	Yr	Reference
Cytosolic	BA	NA	5	5 M	5 M	United States	1982	[30]
Cytosolic and nuclear	BA	NA	5	3 M, 2 F	3 M, 2 F	United Kingdom	1983	[31]
Cytosolic	IHC	NA, Anti ER Ab Hypolabs, Switzerland	10	NA	1	Singapore	1984	[39]
Cytosolic	BA	NA	30	29 M, 1 F	12	Japan	1986	[13]
Cytosolic and nuclear	BA	NA	8	6 M, 2 F	1 M	Japan	1986	[17]
Cytosolic	BA	NA	13	9 M, 4 F	1 F	Japan	1987	[32]
Cytosolic	EIA	Abbot ER-EIA monoclonal kit	13	9 M, 4 F	3 M, 2 F	Japan	1987	[32]
Cytosolic	BA	NA	19	19 F	7 F	Japan	1989	[15]
Cytosolic	BA	NA	66	52 M, 14 F	23 M, 3 F	Japan	1990	[34]
Cytosolic	BA	NA	6	4 M, 2 F	1 F	Japan	1990	[35]
Cytosolic	BA	NA	21	18 M, 3 F	9 M, 1 F	Japan	1991	[36]
Cytosolic and nuclear	BA	NA	9	6 M, 3 F	6 M, 2 F	Italy, United States	1991	[37]
Cytosolic and nuclear	BA	NA	9	6 M, 3 F	6 M, 2 F	Italy, United States	1991	[33]
NA	IHC	NA, Abott, ER-ICA	15	12 M, 3 F	0	Italy	1993	[40]
Cytosolic	EIA	NA, Abbot anti ER	26	18 M, 8 F	4	Spain	1993	[41]
Cytosolic	EIA	NA, Abbot anti ER	33	20 M, 13 F	8 M, 5 F	Germany	1997	[42]
Cytosolic	IHC	NA, ER monoclonal Ab, Dako	71	59 M, 12 F	15 M, 2 F	Hong Kong	1997	[43]
Cytosolic and nuclear	IHC	ERα, Santacruz	45	37 M, 8 F	21 (cytosolic)	United States, Korea1	2004	[44]
					11 (nuclear)
NA	IHC	NA	28	NA	11	China	2004	[45]
NA	IHC	NA	66		3	Mexico	2007	[46]
Nuclear	IHC	ERα, Dako (ID5)	31	26 M, 5 F	12 M, 4 F	Spain	2007	[47]

ER: Estrogen receptor; BA: Binding assay; EIA: Enzyme immunoassay; IHC: Immunohistochemistry; n: Sample size; M: Male; F: Female; NA: Information not available; Ab: Antibody.

¹Study conducted in USA on patient population from Korea.

Table 2 Messenger RNA (mRNA) expression of estrogen receptor in liver tissue samples from HCC patients

Method	ER subtype	n	Subjects	Positive cases	Country	Yr	Reference
ISH	ERα Wt	15	12 M, 3 F	11	Italy	1993	[40]
RT-PCR	ERα Wt	14	7 M, 7 F	1 M, 7 F	Italy	1995	[51]
RT-PCR	ERα delta5 variant	14	7 M, 7 F	7 M, 3 F	Italy	1995	[51]
RT-PCR	ERα Wt	40	25 M, 15 F	16 M, 12 F	Italy	1998	[18]
RT-PCR	ERα delta5 variant	40	25 M, 15 F	20 M, 10 F	Italy	1998	[18]
RT-PCR	ERα Wt	42	35 M, 7 F	20 M, 5 F	Italy	2003	[19]
RT-PCR	ERα delta5 variant	42	35 M, 7 F	37	Italy	2003	[19]
RT-PCR	ERβ Wt	42	35 M, 7 F	12 M, 4 F	Italy	2003	[19]
RT-PCR	ERα Wt	28	NA	25	China	2004	[45]
RT-PCR	ERα delta5 variant	28	NA	27	China	2004	[45]
RT-PCR	ERα Wt	32	23 M, 9 F	23 M, 9 F	Korea	2006	[52]
RT-PCR	ERα delta5 variant	32	23 M, 9 F	21 M, 9 F	Korea	2006	[52]
RT-PCR	ERβ Wt	32	23 M, 9 F	26	Korea	2006	[52]

ER: Estrogen receptor; ISH: In situ hybridization; RT-PCR: Reverse transcriptase-polymerase chain reaction; Wt: Wild type; n: Sample size; M: Male; F: Female; NA: Information not available.

Table 3 Estrogen receptor and androgen receptor expression in normal and non-cancerous liver tissue samples

Receptor protein/mRNA	Type of liver tissue	Subjects	Positive cases	Method	Country	Yr	Reference
Estrogen Receptor (ER)
ER protein (cytosolic)	Normal liver tissue	4 F	4 F	BA	United Kingdom	1978	[28]
ER protein	Normal	3 F	3 F	BA	Germany	1978	[59]
ER protein	Normal	2 M	2 M	BA	United States	1982	[30]
ER protein	Normal	1 M, 5 F	1 M, 5 F	BA	Germany	1982	[60]
ER protein	Normal	3 M, 3 F	3 M, 3 F	BA	United States	1983	[61]
ER protein (cytosolic & nuclear)	Normal	2 M, 2 F	2 M, 2 F	BA	United Kingdom	1983	[31]
ER protein (cytosolic)	Surrounding liver tissue	30	13	BA	Japan	1986	[13]
ER protein (cytosolic & nuclear)	Non-cancerous tissue	7	3	BA	Japan	1986	[17]
ER protein (cytosolic & nuclear)	Normal	NA	NA	BA	United States	1987	[62]
ER protein (cytosolic)	Non-cirrhotic liver	5 M, 7 F	5 M, 7 F	BA, EIA	Japan	1987	[32]
ER protein	Normal	2	2		Japan	1988	[63]
ER protein (cytosolic)	Surrounding liver tissue	17	11	BA	Japan	1989	[15]
ER protein	Surrounding non-cancerous tissue	22	14	NA	Japan	1989	[64]
ER protein (cytosolic)	Surrounding normal liver	4 M, 1 F	4 M, 1 F	BA	Japan	1990	[35]
ER protein	Adjacent normal tissue	6 M, 3 F	6 M, 3 F	BA	Italy, United States	1991	[33]
ER protein (cytosolic)	Non-tumoral liver	18 M, 8 F	9 M, 2 F	BA	Spain	1993	[41]
ER mRNA	Non-tumorous liver tissue	13	7	ISH	Italy	1993	[40]
ER mRNA	Peri-tumor tissue	32	28	RT-PCR	Korea	2006	[52]
Androgen Receptor (AR)
AR protein (cytosolic & nuclear)	Normal	2 M, 2 F	0	BA	United Kingdom	1983	[31]
AR protein (cytosolic & nuclear)	Non-cancerous tissue	6	1	BA	Japan	1986	[17]
AR protein (cytosolic)	Non-neoplastic liver tissues	17	11	BA	Japan	1989	[15]
AR protein	Surrounding non-cancerous tissues	21	7	NA	Japan	1989	[64]
AR protein (cytosolic)	Surrounding liver	9 M, 1 F	7 M, 1 F	BA	Japan	1990	[35]
AR protein	Adjacent normal tissue	6 M, 3 F	6 M, 3 F	NA	Italy, United States	1991	[33]
AR mRNA	Peri-tumor tissue	23 M, 9 F	23 M, 9 F	RT-PCR	Korea	2006	[52]

BA: Binding assay; EIA: Enzyme immunoassay; IHC: Immunohistochemistry; M: Male; F: Female; NA: Information not available.

Table 4 Androgen receptor protein and mRNA expression in liver tissue samples from HCC patients

	Subcellular Organelle	Method	n	Subjects	Positive	Country	Yr	Reference
AR protein	Cytosolic and nuclear	BA	5	3 M, 2 F	3 M, 2 F	United Kingdom	1983	[31]
	Cytosolic	IHC	10	NA	5	Singapore	1984	[39]
	Cytosolic	BA	19	19 M	14 M	Japan	1985	[14]
	Cytosolic and nuclear	BA	5	3 M, 2 F	3 M, 2 F	United Kingdom	1985	[65]
	Cytosolic and nuclear	BA	8	6 M, 2 F	2 M, 2 F	Japan	1986	[17]
	Cytosolic	BA	13	8 M, 5 F	8 M, 5 F	United Kingdom	1988	[66]
	Cytosolic	BA	19	19 F	7 F	Japan	1989	[15]
	Cytosolic	BA	45	31 M, 14 F	25 M, 6 F	Japan	1989	[67]
	Cytosolic	BA	11	9 M, 2 F	6 M, 1 F	Japan	1990	[35]
	Cytosolic	BA	21	18 M, 3 F	18	Japan	1991	[36]
	Cytosolic and nuclear	BA	9	6 M, 3 F	6 M, 3 F	Italy, United States	1991	[33]
	Cytosolic	BA	5	3 M, 2 F	3 M, 2F	Japan	1992	[68]
	Cytosolic	BA	26	18 M, 8 F	14	Spain	1993	[41]
	Cytosolic	BA	43	30 M, 13 F	28	Spain	1995	[69]
	NA	BA	32			China	1998	[70]
	Nuclear	IHC	31	26 M, 5 F	18 M, 3 F	Spain	2007	[47]
AR mRNA		ISH	22	16 M, 6 F	13 M, 3 F	Italy	1994	[16]
		RT-PCR	38	24 M, 14 F	21 M, 13 F	Italy	2002	[71]
		RT-PCR	32	23 M, 9 F	23 M, 9 F	Korea	2006	[52]

AR: Androgen receptor; BA: Binding assay; IHC: Immunohistochemistry; ISH: In situ hybridization; RT-PCR: Reverse transcriptase-polymerase chain reaction; n: Sample size; M: Male; F: Female; NA: Information not available.

Table 5 Studies on correlation of estrogen receptor and androgen receptor expression with clinical and pathological parameters in HCC patients

Receptor protein/mRNA expression	Clinical parameter	n	Country	Salient findings	Yr	Reference
ER protein	Serum alpha-fetoprotein, carcinoembryonic antigen, HBV profile, tumor histology	30	Japan	No correlation with any parameter	1986	[13]
ER and AR protein	Serum alpha fetoprotein, HBV markers, histopathology	19	Japan	No correlation	1989	[15]
ER protein	Sex, age, alcohol abuse, underlying liver disease, hepatic functions	66	Japan	No correlation	1990	[34]
	Tumor size, hepatic resection			Large tumor size and higher rate of resection in ER-
	Histopathology			No differences in ER+ and ER-
	Operative mortality, tumor recurrence, long-term survival rate			Similar in ER+ and ER-
ER and AR protein	Intrahepatic recurrence	78	Japan	AR expression strongly associated with intrahepatic recurrence. Weak association with ER expression	1995	[72]
ER protein	Survival after curative resection	28	Germany	Negative effect of an ER+ tumor on patient survival after curative resection	1997	[42]
Wild type and variant ER mRNA	Survival	96	Italy	Significantly long survival in patients with wild type ERs than variant ERs	2000	[55]
AR protein	Recurrence rate	45	Japan	Significantly higher recurrence rates in AR+ group than AR-	1989	[15]
	Survival rate			Significantly better survival rates in AR- patients than in AR+
AR protein	Tumor size	43	Spain	AR expression was significantly related to smaller tumor size	1995	[69]
	Tumor recurrence			Higher tumor recurrence rates in surrounding tissues of AR+ than AR-
AR protein	Tumor size and survival time	32	China	Survival rate correlated inversely with the levels of AR expression	1998	[70]
				AR levels had positive correlation with the tumor size

Table 6 Clinical outcome of hormonal therapeutic trials in HCC patients

Receptor protein/mRNA expression	Clinical parameter	Treatment	n	Country	Salient Findings	Yr	Reference
ER protein	Tumor growth	Progestin	5	United States	Tumor regression in 2	1982	[30]
NA	Anti-tumor response	Tamoxifen 20 mg twice daily	33	United States	No complete or partial antitumor response	1990	[73]
	Survival time				Long term survival (18+ to 39+ mo) in 4 patients
NA	Anti-tumoral effect	Tamoxifen 20 mg daily	120 (placebo = 62)	Spain	No-antitumor effect	1995	[74]
	Survival time				No significant differences in survival rate of placebo and treated groups
Wild type and variant ER mRNA	Tumor size and growth rate	Tamoxifen 80 mg daily or Megestrol 160 mg daily	8	Italy	Growth rate 4 times higher in tumors expression variant ER than wild type ERs. Tumor regression to half size in patients with wild type ER following tamoxifen treatment. Megestrol slowed down tumor growth in tumors with variant ERs	1996	[54]
ER protein	Mortality rates	Tamoxifen	119 (placebo = 58)	China	No difference in 1 mo mortality rates and median survival in treated and control groups	2000	[75]
	Survival				No effect of ER expression on survival
Variant ER mRNA	Tumor growth, survival	Megestrol 160 mg daily	24 placebo, 21 treated	Italy	Significantly slowed down tumor growth and improved survival in treated patients than placebo group	2001	[76]
NA	Survival rates	Tamoxifen 120 mg daily or 60 mg daily	329	Singapore	No positive effect on survival and increasingly negative impact with increasing doses	2005	[77]

NA: Information not available.