Original article

BMPR1B Polymorphisms (rs1434536 and

rs1970801) are Associated With Breast Cancer
Susceptibility in Northwest Chinese Han Females:
A Case-Control Study
Yi Zheng,1,2,† Xun Jiang,1,† Meng Wang,2 Si Yang,2 Yujiao Deng,2 Yizhen Li,2
Zhen Zhai,2 Ying Wu,1 Nan Wang,2 Xueting Ren,2 Huafeng Kang,2 Lei Chen1,2
Abstract
This study is aimed to explore the relationship between BMPR1B polymorphisms (rs1434536 and rs1970801)
and breast cancer susceptibility among northwest population. A total of 450 healthy controls and 434 patients
with breast cancers were recruited in this study. We found BMPR1B polymorphisms (rs1434536 and rs1970801)
may increase susceptibility to breast cancer in Chinese Han women.
Background: Bone morphogenetic proteins receptor type 1B (BMPR1B) was a multifunctional signaling molecule and
its abnormal expression associated with poorer prognosis. We aimed to explore the relationship between BMPR1B
polymorphisms and breast cancer susceptibility among northwest population. Methods: A total of 450 healthy controls
and 434 patients with breast cancers were recruited in this study. Two candidate polymorphisms, rs1434536 and
rs1970801 were genotyping using Sequenom MassArray technique. Expression quantitative trait loci analysis in the
GTEx portal was adopted to determine the correlation between the rs1434536 and rs1970801 polymorphism and level
of BMPR1B expression. Results: We found that the T allele of rs1434536 was associated with an increased suscepti-
bility of breast cancer [CT+TT vs. CC: adjusted OR (95% CI) = 1.35(1.02-1.78), Padjusted = 0.034; CT vs. CC adjusted
OR (95% CI) = 1.39(1.03-1.87), Padjusted = 0.029]. For rs1970801, carrying minor allele T was significantly associated
with an increased risk of breast cancer [GT+TT vs. GG: adjusted OR (95% CI) = 1.52(1.14-2.01), Padjusted = 0.004;
GT vs. GG adjusted OR (95% CI) = 1.56(1.15-2.09), Padjusted = 0.004]. Stratified analyses found statistical significance
existing in women under 49 years of age, BMI less than 24 kg/m2 , and premenopausal women for both rs1434536 and
rs1970801. Expression quantitative trait loci analysis in the GTEx portal proved that the minor alleles of rs1434536 T
and rs1970801 T was significantly associated with higher expression level of BMPR1B. Conclusion: BMPR1B polymor-
phisms (rs1434536 and rs1970801) may increase susceptibility to breast cancer in Chinese Han women.

Clinical Breast Cancer, Vol. 22, No. 5, e641–e646 © 2022 Elsevier Inc. All rights reserved.
Keywords: Genetic susceptibility, Molecular epidemiology, Cancer research, Case-control study, Single nucleotide
polymorphism

Introduction
Abbreviations: BMPR1B, bone morphogenetic proteins receptor type 1B; SDI, social- According to the data from Cancer Statistics, 2021, 284,200 newly
development index; BMPs, bone morphogenetic proteins; TGF-β, transforming diagnosed breast cancer and 44,130 breast cancer related death were
growth factor β; UTR, untranslated region; eQTL, expression quantitative trait
loci; HWE, Hardy-Weinberg Equilibrium; BMI, body mass index; OR, Odds ratio; estimated to occur among American women in 2021.1 As the most
CI, confidence interval; Erk, extracellular signal regulated kinase; MAPK, mitogen- common malignant tumor in women, breast cancer has brought
activated protein kinase.
1
heavy burdens for world public health, especially in lower social-
Department of General Surgery, the Tenth People’s Hospital, Tongji University,
Shanghai, China development index countries.2 Because of its unique metastasis to
2
Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong bone, the involvement of bone morphogenetic proteins (BMPs) in
University, Xi’an, China
breast cancer progression has been widely studied.3-5 BMPs and their
Submitted: Oct 24, 2021; Revised: Jan 3, 2022; Accepted: Feb 25, 2022; Epub: 14
March 2022 receptors are involved in complex signal pathways in human organs
Address for correspondence: Lei Chen Attending physician, Department of General development and mature.6 Genetic mutations of BMPs signals are
Surgery, the Tenth People’s Hospital, Tongji University, Shanghai 200072, China
E-mail contact: kanghuafeng1973@126.com, trillen@163.com
E-mail contact: kanghuafeng1973@126.com, trillen@163.com
Address for correspondence: Huafeng Kang MD Tutor, Department of Oncology, The
†
Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China Y Z and X J contributed equally to this work.

1526-8209/$ - see front matter © 2022 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.clbc.2022.02.011 Clinical Breast Cancer July 2022 e641
 BMPR1B Polymorphisms With Breast Cancer Susceptibility
associated with various human disease, including many types of
cancers.7
BMP receptor type 1B (BMPR1B), also known as ALK6, encodes
a member of the BMP type I receptors. BMPR1B is a multifunc-
tional signaling molecule served as a receptor of BMP ligands,
which constitute a large subdivision of transforming growth factor
β (TGF-β) superfamily. Previous research indicated that overex-
pression of BMPR1B was associated with higher tumor grade
and poorer prognosis.8 SNPs in 3 untranslated region (UTR) of
tumor-associated genes might alter the regulation of microRNA
(miRNA) and lead to carcinogenesis.9 We selected 2 polymor-
phisms (rs1434536 and rs1970801) in 3 UTR of BMPR1B gene to
study the relationship between them and breast cancer, which were
reported may increase the risk of prostate cancer, 10 endometriosis,
11
and microtia.12
However, the association between rs1434536 and rs1970801 in
BMPR1B and breast cancer risk among northwest Chinese Han
population was still not clear. Thus, we performed this population-
based case-control study to explore the correlation between the 2
BMPR1B polymorphisms (rs1434536 and rs1970801) and breast
cancer. Furthermore, we adopted expression quantitative trait loci
(eQTL) analysis in the GTEx portal to determine the correlation
between the rs1434536 and rs1970801 polymorphism and level of
BMPR1B expression.
Materials and Methods
Study Subjects
Breast cancer patients (n = 434) were recruited from the Second
Affiliated Hospital of Xi’an Jiaotong University during 2013 to
2015. All 434 patients with breast cancer were newly diagnosed
and confirmed by cytology, histopathology and microscopic without
distant metastatic. Patients who previously diagnosed as other
cancers or had undergone preoperative chemotherapy or radiother-
apy were excluded. Controls (n = 450) were age-matched healthy
individuals who underwent a checkup at the same hospital during
the same period of time. The controls had no history of malignant
tumors or other diseases, no obvious abnormal in blood routine
examination. All enrolled subjects were Han Chinese women and
supplied a written informed consent. Clinical information was
collected from the medical records of the study subjects.
SNP Selection and Genotyping
First, we selected SNPs from NCBI dbSNP database (https:
//www.ncbi.nlm.nih.gov/projects/SNP) and miRNA SNP V3
database (http://bioinfo.life.hust.edu.cn/miRNASNP/#!/).13 The
screening criteria were as following: (1) the SNPs were located
in 3 UTR of BMPR1B, (2) the minor allele frequency was no
less than 0.25 among European population from the data of
1000Genomes,14 (3) located in GWAS LD region. A total of 7
SNPs (rs2289044, rs1836261, rs11097457, rs1434536, rs1434535,
rs1863654, and rs2162450) of BMPR1B meet the above selected
criteria. Then, we searched the literature and found that rs1434536
was reported to affect the expression of BMPR1B.11 Moreover, we
selected another SNP rs1970801 located in the 3 UTR of BMPR1B
because it was reported associated with breast cancer.15 Finally,
we selected rs1434536 and rs1970801 to study. Every enrolled
e642 Clinical Breast Cancer July 2022
participant donated 5 ml peripheral blood sample. The samples
were collected in EDTA-coated tubes and conserved at -80°C.
Genome DNA were extracted from whole blood samples using
ComWin BloodGen Mini Kit (QIAGEN, China, Beijing). The
purity and concentration of extracted DNA was measured by ultra-
violet spectrophotometer (Nanodrop, Thermo Scientific, Waltham,
MA). We designed multiplexed SNP MassEXTEND assay using
Sequenom MassARRAY Assay Design 3.0 software. DNA samples
were genotyped by Sequenom MassARRAY RS1000 according to
the standard protocol. Primers used for rs1434536 and rs1970801
are listed in Supplemental Table S1.
Statistical Analysis
Fisher’s exact test was applied to calculate the Hardy-Weinberg
Equilibrium (HWE) of rs1434536 and rs1970801. The differ-
ence of age distribution and body mass index (BMI) between BC
patients and healthy controls was evaluated by student’s t test.
Two-sided Pearson’s chi-square tests were adopted to access the
differences in the categorical variables between cases and controls,
such as age (≤49 and >49), BMI, menstrual-status, and allelic
frequencies. It was considered statistically significant if P value less
than .05. Odds ratios and 95% confidence intervals were calcu-
lated to evaluated the strength of the association between the 2
polymorphisms of BMPR1B and breast cancer. We used uncon-
ditional univariate and multivariate logistic regression analyses to
estimate the strength of the association between the rs1434536 and
rs1970801 polymorphism and breast cancer risk, adjusting for age,
BMI, and menopausal status. All statistical analyses were two-sided
and performed by SPSS 18.0 software.
Genotype-Phenotype Correlation Analysis
Expression quantitative trait loci (eQTL) is a region of the
genome containing DNA sequence variations that affect gene
expression. The most comprehensive eQTL database to date is
GTEx (https://www.gtexportal.org/home/), which has now been
updated to the 18th edition. We searched in the GTEx portal to
access the influence of rs1434536 and rs1970801 polymorphism on
the expression level of BMPR1B.
Results
Demographical and Clinical Information of Study
Population
In total, this study included 434 breast cancer patients (mean age
of 51.95 ± 10.35) and 450 healthy controls (mean age of 50.66
± 9.57). All participants were Northwest Han Chinese women.
No statistically significance was found in age distribution, BMI
and menopausal status between cases and controls. There were 114
(26.3%), 192 (44.2%), 89 (20.5%) and 39 (9.0%) breast cancer
patients in tumor clinical stage I, II, III, and IV, respectively. The
detail demographical and clinical information of participants were
displayed in Table 1.
The Association Between BMPR1B SNPs and BC Risk
The respond rates of BMPR1B rs1434536 and rs1970801 are
98.5% and 98.4%, respectively. Genotype frequencies of the 2 SNPs
among controls were in accordance with HWE (P > .05). The allele
 Yi Zheng et al
Table 1 Demographic Information

Characteristics Cases (%) Control (%) P value

Number 434 450
Age (mean ± SD) 51.95 ± 10.35 50.66 ± 9.57 0.148a
≤49 180(41.5) 202(44.9)
>49 254(58.5) 248(55.1) 0.306b
BMI, kg/m2 (mean ± SD) 22.38 ± 2.61 22.75 ± 5.08 0.172a
Menopausal status
Premenopausal 157(36.2) 188(41.8)
Postmenopausal 277(63.8) 262(58.2) 0.088b
TNM Stage
Ⅰ 114(26.3) - -
Ⅱ 192(44.2) - -
Ⅲ 89(20.5) - -
Ⅳ 39(9) - -
Immunohistochemistry results
ER – 142(32.7) -
+ 292(67.3) -
PR – 189(43.5) -
+ 245(56.5) -
Her-2 – 250(57.6) -
+ 184(42.4) -

Abbreviations: BMI = body mass index; ER = estrogen receptor; Her-2 = human epidermal growth factor receptor-; 2PR = progesterone receptor.
a
Student’s t test
χ test for genotype distributions between breast cancer patients and controls.
b 2

Table 2 Association Between BMPR1B Polymorphisms and Risk of Breast Cancer (rs1434536 and rs1970801)

Genotype Cases (%) Controls (%) Pa Crude OR (95%CI) P Adjusted OR (95%)b Pb

rs1434536 HWE = 0.057
CC 157(36.9) 199(44.6) 1 1
CT 206(48.5) 184(41.3) 1.42(1.06-1.49) 0.017 1.39(1.03-1.87) 0.029
TT 62(14.6) 63(14.1) 1.25(0.83-1.88) 0.289 1.26(0.83-1.92) 0.277
Dominant 268(63.1) 247 (55.4) 0.021 1.38(1.05-1.80) 0.021 1.35(1.02-1.78) 0.034
Recessive 363(85.4) 383 (85.9) 0.846 1.04(0.71-1.52) 0.846 1.05(0.71-1.54) 0.805
rs1970801 HWE = 0.061
GG 142(33.3) 192(43.2) 1 1
GT 215(50.5) 186(41.9) 1.56(1.17-2.09) 0.003 1.56(1.15-2.09) 0.004
TT 69(16.2) 66(14.9) 1.41(0.95-2.11) 0.091 1.41(0.93-2.12) 0.104
Dominant 284(66.7) 252 (56.8) 0.003 1.52(1.16-2.01) 0.003 1.52(1.14-2.01) 0.004
Recessive 357(83.8) 378 (85.1) 0.587 1.11(0.77-1.60) 0.588 1.13(0.77-1.64) 0.536

Abbreviations: CI = confidence interval; OR = odds ratio.

χ test for genotype distributions between breast cancer patients and controls.
a 2
b
Adjusted for age, BMI and menopausal status.

distribution and association between BMPR1B polymorphisms and
breast cancer were presented in Table 2.
We found that the T allele of rs1434536 was associated with
increased susceptibility of breast cancer (CT vs. CC: adjusted
OR = 1.39, 95% CI = 1.03-1.87, P = .029; TT + CT vs.
CC: adjusted OR = 1.35, 95% CI = 1.02-1.78, P = .034). For
rs1970801, carrying minor allele T was significantly associated with
an increased risk of breast cancer (GT vs. GG: adjusted OR = 1.56,
95% CI = 1.15-2.09, P = .004; TT + GT vs. GG: adjusted
OR = 1.52, 95% CI = 1.14-2.01, P = .004).
Stratified Analysis by Age, BMI and Menopausal Status
To further explore the correlation between BMPR1B polymor-
phisms and breast cancer, we performed stratified analysis based on
age, BMI and menopausal status. We divided BMI into 2 groups
(BMI <24 kg/m2 and BMI ≥24 kg/m2 ). For rs1434536, statis-

Clinical Breast Cancer July 2022 e643

 BMPR1B Polymorphisms With Breast Cancer Susceptibility
Figure 1 Stratified Analysis of rs1434536 and rs1970801on BMPR1B by age, BMI and menopausal status. CI = confidence
interval; OR = odds ratio. Adjusted by age, BMI and menopausal status.
tical significance was found in the following subgroups: women
under 49 years of age (adjusted OR = 1.98, 95% CI = 1.28-
3.06, P = .002), BMI less than 24 kg/m2 (adjusted OR = 1.52,
95% CI = 1.09-2.14, P = .015), and premenopausal women
(adjusted OR = 2.11, 95% CI = 1.32-3.37, P = .002). Similar
results were found in rs1970801, the detail results were shown in
Figure 1.
Relationship Between BMPR1B SNPs and Clinical
Characteristics of Breast Cancer
Then, we conducted correlation analysis to evaluate the effect of
the 2 BMPR1B SNPs and clinical characteristics on breast cancer
risk, including age, BMI, menopausal status, tumor size, metasta-
sis, TNM stage, and immunohistochemistry results (ER, PR and
Her-2). There were no association found between BMPR1B SNPs
(rs1434536 and rs1970801) and clinical characteristics of breast
cancer (as shown in Supplement Table S2).
Effect of rs1434536 and rs1970801 on the Expression of
BMPR1B
We further assessed the functional relevance of rs1434536 and
rs1970801 using released data from GTEx. The results indicated
that the minor alleles of rs1434536 T and rs1970801 T was
significantly associated with higher expression level of BMPR1B
(Figure 2).
Discussion
This case-control study based on 834 participants and we found
that the minor alleles of rs1434536 and rs1970801 was associated
with an increased susceptibility of breast cancer. eQTL analysis in
the GTEx portal proved that the minor alleles of rs1434536 T
e644 Clinical Breast Cancer July 2022
and rs1970801 T was significantly associated with higher expression
level of BMPR1B. Stratified analyses found statistical significance
existed in women under 49 years of age, BMI less than 24 kg/m2 ,
and premenopausal women for both rs1434536 and rs1970801.
BMPs were first reported for their ability to induce ectopic
bone formation.16 They constitute the largest subdivision of TGF-
β superfamily, play a critical role in bone formation, angiogen-
esis, and maintaining homeostasis by mediating cell differenti-
ation, proliferation, survival and motility.17 BMPs ligands were
activated via recruiting and binding to their type I and type II
serine/threonine kinase receptors, and ultimately forming the BMP
transmembrane signaling complex.18-20 Activation of BMP trans-
membrane signaling complex subsequently results in phosphoryla-
tion of the receptor-activated Smads 1, 5, and 8 (R-Smads) along
with other pathways including extracellular signal regulated kinase,
p38 mitogen-activated protein kinase, and PI3K-Akt.17 , 21-23 These
mechanisms were involved in various type of cancer development
including breast cancer.24 , 25 The members of BMPs family play
different roles in breast cancer. For example, BMP-2 and BMP-4 can
inhibit the proliferation of breast cancer cells, but can also promote
breast cancer invasion and metastasis.20 In contrast, BMPs receptors
such as BMPR1A, BMPR2 and BMPR1B appear to promote cancer
progression.8 Among these, BMPR1B is a multifunctional signaling
molecule served as one of the 4 type I receptors of BMPs and it
can affect cell differentiation, proliferation, survival and apoptosis
by regulating BMPs signals. Moreover, overexpression of BMPRIB
is related to high tumor grade, proliferation, cytogenetic instability,
and a poor prognosis in ER+ breast carcinomas.26
In this study, we aimed to investigate the association between
BMPR1B polymorphisms and breast cancer. We selected 2
polymorphisms (rs1434536 and rs1970801) near the 3 UTR of

Figure 2 Functional relevance of rs1434536 and rs1970801 on the expression of its neighboring gene BMPR1B in GTEx
database. (A) for rs1434536; (B) for rs1970801.
BMPR1B gene. In general, miRNA can achieve posttranscriptional
regulation by binding to the 3 UTR of their targeted gene and
eventually influence the expression of the genes.27 MiR-125b was
found binding to 3 UTR of BMPR1B gene and it could negatively
regulate the expression of BMPR1B.26 The T allele of rs1434536 in
the region of 3 UTR BMPR1B can disturb the regulation of miR-
125b, lead to BMPR1B overexpression, and consequently increase
the risk of diseases. These research results can support our results
and further explain the functional regulation mechanism of the 2
SNPs regulating BMPR1B expression and affecting breast cancer
susceptibility.
However, there are still some potential limitations should be clari-
fied. Firstly, the enrolled population is under-represented because
the participants recruited in this investigation are from Xi’an
and surrounding areas. Secondly, some potential risk factors from
environmental, lifestyle and other social status were failed to be
considered in this study, which may have an influence on the
study results. Thirdly, this is a one center case-control study with a
relatively limited sample scale, unpredictable selective bias may exist
in the results.
Conclusion
BMPR1B polymorphisms (rs1434536 and rs1970801) may
increase susceptibility to breast cancer in Chinese Han women.
Clinical Practice Points
• Previous studies found that rs1434536 and rs1970801 located in
the 3 UTR of the BMPR1B and was associated with breast cancer
pathogenesis.
• This is the first population-based case-control study to explore the
correlation between the 2 BMPR1B polymorphisms (rs1434536
and rs1970801) and breast cancer among Chinese Northwest
population. We found that carrying minor alleles of rs1434536
and rs1970801 was associated with an increased susceptibility of
Yi Zheng et al
breast cancer. eQTL analysis in the GTEx portal proved that the
minor alleles of rs1434536 T and rs1970801 T was significantly
associated with higher expression level of BMPR1B.
• We provided an evidence of an association of BMPR1B polymor-
phisms (rs1434536 and rs1970801) and breast cancer among
Chinese Northwest population. Our findings have potential
implications in genetic counseling, breast cancer screening and
prognosis.
Ethics Approval and Consent to
Participate
The protocol of this study and all the relevant data adhere to
the ethical code of scientific research in China. It was approved by
the Ethics Committee of the Second Affiliated Hospital of Xi’an
Jiaotong University Shaanxi Province (Xi’an, China, No 2018-
1987). All patients gave written informed consent prior to partic-
ipation in the study.
Consent for Publication
Not applicable.
Availability of Data and Materials
The datasets generated during and/or analyzed during the current
study have been submitted as related files to the editors.
Acknowledgments
The authors thank all members of our study team for their whole-
hearted cooperation and all included participants for their wonder-
ful cooperation.
Author Contributions
HFK and LC contributed to study design and the experiments
guide. YZ contributed to sample collected, data collection, data
analysis, data interpretation, and writing of the manuscript. XJ
Clinical Breast Cancer July 2022 e645
 BMPR1B Polymorphisms With Breast Cancer Susceptibility
contributed to sample collected, data collection and SNP detected.
MW, SY, YJD, and YZL collected the samples. ZZ, YW, NW, and
XTR extracted DNA and detected the SNPs. All authors read and
approved the final manuscript.
Disclosure
We declare no conflicts of interest for this study.
Supplementary materials
Supplementary material associated with this article can be found,
in the online version, at doi:10.1016/j.clbc.2022.02.011.
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